Methods for treating cancer using TOR kinase inhibitor combination therapy

ABSTRACT

Provided herein are methods for treating or preventing a cancer, comprising administering an effective amount of a TOR kinase inhibitor and an effective amount of N-(3-(5-fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4-ylamino)phenyl)acrylamide to a patient having a cancer.

This application claims the benefit of U.S. Provisional Application No.61/813,100, filed Apr. 17, 2013 and U.S. Provisional Application No.61/908,389, filed Nov. 25, 2013, the entire contents of which areincorporated herein by reference.

1. FIELD

Provided herein are methods for treating or preventing a cancercomprising administering an effective amount of a TOR kinase inhibitorand an effective amount ofN-(3-(5-fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4-ylamino)phenyl)acrylamideto a patient having a cancer.

2. BACKGROUND

The connection between abnormal protein phosphorylation and the cause orconsequence of diseases has been known for over 20 years. Accordingly,protein kinases have become a very important group of drug targets. SeeCohen, Nature, 1:309-315 (2002). Various protein kinase inhibitors havebeen used clinically in the treatment of a wide variety of diseases,such as cancer and chronic inflammatory diseases, including diabetes andstroke. See Cohen, Eur. J. Biochem., 268:5001-5010 (2001), ProteinKinase Inhibitors for the Treatment of Disease: The Promise and theProblems, Handbook of Experimental Pharmacology, Springer BerlinHeidelberg, 167 (2005).

The protein kinases are a large and diverse family of enzymes thatcatalyze protein phosphorylation and play a critical role in cellularsignaling. Protein kinases may exert positive or negative regulatoryeffects, depending upon their target protein. Protein kinases areinvolved in specific signaling pathways which regulate cell functionssuch as, but not limited to, metabolism, cell cycle progression, celladhesion, vascular function, apoptosis, and angiogenesis. Malfunctionsof cellular signaling have been associated with many diseases, the mostcharacterized of which include cancer and diabetes. The regulation ofsignal transduction by cytokines and the association of signal moleculeswith protooncogenes and tumor suppressor genes have been welldocumented. Similarly, the connection between diabetes and relatedconditions, and deregulated levels of protein kinases, has beendemonstrated. See e.g., Sridhar et al. Pharmaceutical Research, 17(11):1345-1353 (2000). Viral infections and the conditions relatedthereto have also been associated with the regulation of proteinkinases. Park et al. Cell 101 (7): 777-787 (2000).

Because protein kinases regulate nearly every cellular process,including metabolism, cell proliferation, cell differentiation, and cellsurvival, they are attractive targets for therapeutic intervention forvarious disease states. For example, cell-cycle control andangiogenesis, in which protein kinases play a pivotal role are cellularprocesses associated with numerous disease conditions such as but notlimited to cancer, inflammatory diseases, abnormal angiogenesis anddiseases related thereto, atherosclerosis, macular degeneration,diabetes, obesity, and pain.

Protein kinases have become attractive targets for the treatment ofcancers. Fabbro et al., Pharmacology & Therapeutics 93:79-98 (2002). Ithas been proposed that the involvement of protein kinases in thedevelopment of human malignancies may occur by: (1) genomicrearrangements (e.g., BCR-ABL in chronic myelogenous leukemia), (2)mutations leading to constitutively active kinase activity, such asacute myelogenous leukemia and gastrointestinal tumors, (3) deregulationof kinase activity by activation of oncogenes or loss of tumorsuppressor functions, such as in cancers with oncogenic RAS, (4)deregulation of kinase activity by over-expression, as in the case ofEGFR and (5) ectopic expression of growth factors that can contribute tothe development and maintenance of the neoplastic phenotype. Fabbro etal., Pharmacology & Therapeutics 93:79-98 (2002).

The elucidation of the intricacy of protein kinase pathways and thecomplexity of the relationship and interaction among and between thevarious protein kinases and kinase pathways highlights the importance ofdeveloping pharmaceutical agents capable of acting as protein kinasemodulators, regulators or inhibitors that have beneficial activity onmultiple kinases or multiple kinase pathways. Accordingly, there remainsa need for new kinase modulators.

The protein named mTOR (mammalian target of rapamycin), which is alsocalled FRAP, RAFTI or RAPT1), is a 2549-amino acid Ser/Thr proteinkinase, that has been shown to be one of the most critical proteins inthe mTOR/PI3K/Akt pathway that regulates cell growth and proliferation.Georgakis and Younes Expert Rev. Anticancer Ther. 6(1):131-140 (2006).mTOR exists within two complexes, mTORC1 and mTORC2. While mTORC1 issensitive to rapamycin analogs (such as temsirolimus or everolimus),mTORC2 is largely rapamycin-insensitive. Notably, rapamycin is not a TORkinase inhibitor. Several mTOR inhibitors have been or are beingevaluated in clinical trials for the treatment of cancer. Temsirolimuswas approved for use in renal cell carcinoma in 2007 and sirolimus wasapproved in 1999 for the prophylaxis of renal transplant rejection.Everolimus was approved in 2009 for renal cell carcinoma patients thathave progressed on vascular endothelial growth factor receptorinhibitors, in 2010 for subependymal giant cell astrocytoma (SEGA)associated with tuberous sclerosis (TS) in patients who require therapybut are not candidates for surgical resection, and in 2011 forprogressive neuroendocrine tumors of pancreatic origin (PNET) inpatients with unresectable, locally advanced or metastatic disease.There remains a need for TOR kinase inhibitors that inhibit both mTORC1and mTORC2 complexes.

DNA-dependent protein kinase (DNA-PK) is a serine/threonine kinaseinvolved in the repair of DNA double strand breaks (DSBs). DSBs areconsidered to be the most lethal DNA lesion and occur endogenously or inresponse to ionizing radiation and chemotherapeutics (for review seeJackson, S. P., Bartek, J. The DNA-damage response in human biology anddisease. Nature Rev 2009; 461:1071-1078). If left unrepaired, DSBs willlead to cell cycle arrest and/or cell death (Hoeijmakers, J. H. J.Genome maintenance mechanisms for preventing cancer. Nature 2001; 411:366-374; van Gent, D. C., Hoeijmakers, J. H., Kanaar, R. Chromosomalstability and the DNA double-stranded break connection. Nat Rev Genet.2001; 2: 196-206). In response to the insult, cells have developedcomplex mechanisms to repair such breaks and these mechanisms may formthe basis of therapeutic resistance. There are two major pathways usedto repair DSBs, non-homologous end joining (NHEJ) and homologousrecombination (HR). NHEJ brings broken ends of the DNA together andrejoins them without reference to a second template (Collis, S. J.,DeWeese, T. L., Jeggo P. A., Parker, A. R. The life and death of DNA-PK.Oncogene 2005; 24: 949-961). In contrast, HR is dependent on theproximity of the sister chromatid which provides a template to mediatefaithful repair (Takata, M., Sasaki, M. S., Sonoda, E., Morrison, C.,Hashimoto, M., Utsumi, H., et al. Homologous recombination andnon-homologous end joining pathways of DNA double-strand break repairhave overlapping roles in the maintenance of chromosomal integrity invertebrate cells. EMBO J. 1998; 17: 5497-5508; Haber, J. E. Partners andpathways repairing a double-strand break. Trends Genet. 2000; 16:259-264). NHEJ repairs the majority of DSBs. In NHEJ, DSBs arerecognized by the Ku protein that binds and then activates the catalyticsubunit of DNA-PK. This leads to recruitment and activation ofend-processing enzymes, polymerases and DNA ligase IV (Collis, S. J.,DeWeese, T. L., Jeggo P. A., Parker, A. R. The life and death of DNA-PK.Oncogene 2005; 24: 949-961). NHEJ is primarily controlled by DNA-PK andthus inhibition of DNA-PK is an attractive approach to modulating therepair response to exogenously induced DSBs. Cells deficient incomponents of the NHEJ pathway are defective in DSB repair and highlysensitive to ionizing radiation and topoisomerase poisons (reviewed bySmith, G. C. M., Jackson, S. P. The DNA-dependent protein kinase. GenesDev 1999; 13: 916-934; Jeggo, P. A., Caldecott, K., Pidsley, S., Banks,G. R. Sensitivity of Chinese hamster ovary mutants defective in DNAdouble strand break repair to topoisomerase II inhibitors. Cancer Res1989; 49: 7057-7063). A DNA-PK inhibitor has been reported to have thesame effect of sensitizing cancer cells to therapeutically induced DSBs(Smith, G. C. M., Jackson, S. P. The DNA-dependent protein kinase. GenesDev 1999; 13: 916-934).

Bruton's tyrosine kinase (BTK) is a non-receptor tyrosine kinase withrestricted cellular expression largely limited to B-lymphocytes,monocytes, and mast cells or basophils. BTK is a critical component ofthe B-cell receptor (BCR) signaling network and is crucial for B-celldevelopment. Investigation has revealed that some B-cell malignancies,including B-cell non-Hodgkin lymphomas, depend on BCR signaling,suggesting that interruption of such signaling could be a promisingtherapeutic opportunity. Recently, clinical anti-tumor responses invarious B-cell non-Hodgkin lymphoma (B-NHL) and CLL/SLL have beenreported with agents that inhibit spleen tyrosine kinase (SYK) and BTK,both components of the BCR signaling pathway.

Recent preclinical research has shown that BTK is an important signalingprotein in the pathway for lymphomagenesis, especially in certain typesof DLBCL. Recent clinical research has further shown that bothlenalidomide and certain BTK inhibitors exhibit activity in DLBCL andMCL.

Citation or identification of any reference in Section 2 of thisapplication is not to be construed as an admission that the reference isprior art to the present application.

3. SUMMARY

Provided herein are methods for treating or preventing a cancer,comprising administering an effective amount of a TOR kinase inhibitorand an effective amount ofN-(3-(5-fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4-ylamino)phenyl)acrylamide:

or a pharmaceutically acceptable salt thereof (collectively referred toherein as “Compound AA”), to a patient having a cancer. In a particularembodiment, a besylate salt of Compound AA is used in the compositionsand methods provided herein. In a particular embodiment, the free baseof Compound AA is used in the compositions and methods provided herein.

In certain embodiments, provided herein are methods for achieving anInternational Workshop on Chronic Lymphocytic Leukemia (IWCLL) responsedefinition of complete response (CR), complete response with incompletemarrow recovery (CRi), partial response (PR), or stable disease (SD) ina patient having chronic lymphocytic leukemia, comprising administeringan effective amount of a TOR kinase inhibitor in combination withCompound AA to said patient. In certain embodiments, provided herein aremethods for achieving a National Cancer Institute-sponsored WorkingGroup on Chronic Lymphocytic Leukemia (NCI-WG CLL) response definitionof complete response (CR), complete response with incomplete marrowrecovery (CRi), partial response (PR) or stable disease (SD) in apatient having chronic lymphocytic leukemia, comprising administering aneffective amount of a TOR kinase inhibitor in combination with CompoundAA to said patient. In certain embodiments, provided herein are methodsfor achieving an International Workshop Criteria (IWC) for non-Hodgkin'slymphoma of complete response, partial response or stable disease in apatient having non-Hodgkin's lymphoma, comprising administering aneffective amount of a TOR kinase inhibitor in combination with CompoundAA to said patient. In certain embodiments, provided herein are methodsfor achieving an International Uniform Response Criteria (IURC) formultiple myeloma of complete response, partial response or stabledisease in a patient having multiple myeloma, comprising administeringan effective amount of a TOR kinase inhibitor in combination withCompound AA to said patient. In certain embodiments, provided herein aremethods for achieving a Response Evaluation Criteria in Solid Tumors(for example, RECIST 1.1) of complete response, partial response orstable disease in a patient having a solid tumor, comprisingadministering an effective amount of a TOR kinase inhibitor incombination with Compound AA to said patient. In certain embodiments,provided herein are methods for achieving a Prostate Cancer WorkingGroup 2 (PCWG2) Criteria of complete response, partial response orstable disease in a patient having prostate cancer, comprisingadministering an effective amount of a TOR kinase inhibitor incombination with Compound AA to said patient. In certain embodiments,provided herein are methods for achieving a Responses Assessment forNeuro-Oncology (RANO) Working Group for glioblastoma multiforme ofcomplete response, partial response or stable disease in a patienthaving glioblastoma multiforme, comprising administering an effectiveamount of a TOR kinase inhibitor in combination with Compound AA to saidpatient.

In certain embodiments, provided herein are methods for increasingsurvival without cancer progression of a patient having a cancer,comprising administering an effective amount of a TOR kinase inhibitorin combination with an effective amount of Compound AA to said patient.

In certain embodiments, the TOR kinase inhibitor is a compound asdescribed herein.

The present embodiments can be understood more fully by reference to thedetailed description and examples, which are intended to exemplifynon-limiting embodiments.

4. BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts the antitumor activity of Compound 1 in the WSU-DLBCL2xenograft model. Tumor inhibition is shown as a percentage change foreach treatment group and represents the difference in average tumorvolume between Compound 1-treated mice and vehicle-treated mice on Day35. The average tumor volumes of all Compound 1-treated groups weresignificantly smaller than in vehicle-treated control mice on Day 35. Atthe end of the study on Day 35, approximately 51%, 28% and 22% tumorvolume reduction (TVR) was observed at the dose levels of 10, 3 and 1mg/kg, respectively. No significant body weight loss was observed inmice treated with Compound 1.

FIG. 2 depicts the antitumor activity of Compound 1 in combination withCompound A in the WSU-DLCL2 xenograft model. Tumor inhibition is shownas a percentage change for each treatment group and represents thedifference in average tumor volume between Compound 1- and CompoundA-treated mice and vehicle-treated mice on Day 34. Compound 1 at 10mg/kg yielded a statistically significant (p<0.001) decrease in tumorvolume of 29% as a single agent treatment. Compound A at 30 mg/kgyielded a statistically significant (p<0.001) decrease in tumor volumeof 30% as a single agent treatment on day 34. Tumor volumes were furtherdecreased to 64% with Compound 1 in combination with Compound A(p<0.001). Using the fractional product method, Compound 1 incombination with Compound A was determined to be synergistic indecreasing tumor volume. In a 2-way ANOVA analysis with a Bonferronipost test, the tumor volumes of animals treated with Compound 1 (10mg/kg) in combination with Compound A (30 mg/kg) were significantly(p<0.001) smaller when compared with the tumors of animals treated witheither agent alone. No significant body weight loss was observed in micetreated with Compound 1 or Compound A either as single agents or incombination.

FIG. 3 depicts the antitumor activity of Compound 1 in combination withCompound AA in the WSU-DLCL2 xenograft model. Tumor inhibition is shownas a percentage change for each treatment group and represents thedifference in average tumor volume between Compound 1 and CompoundAA-treated mice and vehicle-treated mice on Day 34. Compound 1 at 10mg/kg yielded a statistically significant (p<0.001) decrease in tumorvolume of 29% as a single agent treatment. No significant antitumoractivity of Compound AA at 50 mg/kg (BID) was observed. There was a 39%decrease in the tumor volumes in animals treated with Compound 1 incombination with Compound AA (simultaneous administration) when comparedwith vehicle control group. In a 2-way ANOVA analysis with a Bonferronipost-test this combination effect of Compound 1 and Compound AA whencompared with single agent activity of Compound 1 (10 mg/kg) was notsignificantly different. No significant body weight loss was observed inmice treated with Compound 1 or Compound AA either as single agents orin combination.

5. DETAILED DESCRIPTION 5.1 Definitions

An “alkyl” group is a saturated, partially saturated, or unsaturatedstraight chain or branched non-cyclic hydrocarbon having from 1 to 10carbon atoms, typically from 1 to 8 carbons or, in some embodiments,from 1 to 6, 1 to 4, or 2 to 6 or carbon atoms. Representative alkylgroups include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl and-n-hexyl; while saturated branched alkyls include -isopropyl,-sec-butyl, -isobutyl, -tert-butyl, -isopentyl, 2-methylpentyl,3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl and the like. Examplesof unsaturated alkyl groups include, but are not limited to, vinyl,allyl, —CH═CH(CH₃), —CH═C(CH₃)₂, —C(CH₃)═CH₂, —C(CH₃)═CH(CH₃),—C(CH₂CH₃)═CH₂, —C≡CH, —C≡C(CH₃), —C≡C(CH₂CH₃), —CH₂C≡CH, —CH₂C≡C(CH₃)and —CH₂CC(CH₂CH₃), among others. An alkyl group can be substituted orunsubstituted. In certain embodiments, when the alkyl groups describedherein are said to be “substituted,” they may be substituted with anysubstituent or substituents as those found in the exemplary compoundsand embodiments disclosed herein, as well as halogen (chloro, iodo,bromo, or fluoro); hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino;carboxy; nitro; cyano; thiol; thioether; imine; imide; amidine;guanidine; enamine; aminocarbonyl; acylamino; phosphonato; phosphine;thiocarbonyl; sulfonyl; sulfone; sulfonamide; ketone; aldehyde; ester;urea; urethane; oxime; hydroxylamine; alkoxyamine; aralkoxyamine;N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate;isothiocyanate; cyanate; thiocyanate; B(OH)₂, or O(alkyl)aminocarbonyl.

An “alkenyl” group is a straight chain or branched non-cyclichydrocarbon having from 2 to 10 carbon atoms, typically from 2 to 8carbon atoms, and including at least one carbon-carbon double bond.Representative straight chain and branched (C₂-C₈)alkenyls include-vinyl, -allyl, -1-butenyl, -2-butenyl, -isobutylenyl, -1-pentenyl,-2-pentenyl, -3-methyl-1-butenyl, -2-methyl-2-butenyl,-2,3-dimethyl-2-butenyl, -1-hexenyl, -2-hexenyl, -3-hexenyl,-1-heptenyl, -2-heptenyl, -3-heptenyl, -1-octenyl, -2-octenyl,-3-octenyl and the like. The double bond of an alkenyl group can beunconjugated or conjugated to another unsaturated group. An alkenylgroup can be unsubstituted or substituted.

A “cycloalkyl” group is a saturated, or partially saturated cyclic alkylgroup of from 3 to 10 carbon atoms having a single cyclic ring ormultiple condensed or bridged rings which can be optionally substitutedwith from 1 to 3 alkyl groups. In some embodiments, the cycloalkyl grouphas 3 to 8 ring members, whereas in other embodiments the number of ringcarbon atoms ranges from 3 to 5, 3 to 6, or 3 to 7. Such cycloalkylgroups include, by way of example, single ring structures such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl,2-methylcyclooctyl, and the like, or multiple or bridged ring structuressuch as adamantyl and the like. Examples of unsaturated cycloalkylgroups include cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl,pentadienyl, hexadienyl, among others. A cycloalkyl group can besubstituted or unsubstituted. Such substituted cycloalkyl groupsinclude, by way of example, cyclohexanone and the like.

An “aryl” group is an aromatic carbocyclic group of from 6 to 14 carbonatoms having a single ring (e.g., phenyl) or multiple condensed rings(e.g., naphthyl or anthryl). In some embodiments, aryl groups contain6-14 carbons, and in others from 6 to 12 or even 6 to 10 carbon atoms inthe ring portions of the groups. Particular aryls include phenyl,biphenyl, naphthyl and the like. An aryl group can be substituted orunsubstituted. The phrase “aryl groups” also includes groups containingfused rings, such as fused aromatic-aliphatic ring systems (e.g.,indanyl, tetrahydronaphthyl, and the like).

A “heteroaryl” group is an aryl ring system having one to fourheteroatoms as ring atoms in a heteroaromatic ring system, wherein theremainder of the atoms are carbon atoms. In some embodiments, heteroarylgroups contain 5 to 6 ring atoms, and in others from 6 to 9 or even 6 to10 atoms in the ring portions of the groups. Suitable heteroatomsinclude oxygen, sulfur and nitrogen. In certain embodiments, theheteroaryl ring system is monocyclic or bicyclic. Non-limiting examplesinclude but are not limited to, groups such as pyrrolyl, pyrazolyl,imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl,pyrolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl,benzothiophenyl, furanyl, benzofuranyl (for example,isobenzofuran-1,3-diimine), indolyl, azaindolyl (for example,pyrrolopyridyl or 1H-pyrrolo[2,3-b]pyridyl), indazolyl, benzimidazolyl(for example, 1H-benzo[d]imidazolyl), imidazopyridyl (for example,azabenzimidazolyl, 3H-imidazo[4,5-b]pyridyl or1H-imidazo[4,5-b]pyridyl), pyrazolopyridyl, triazolopyridyl,benzotriazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl,isoxazolopyridyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl,guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl,and quinazolinyl groups.

A “heterocyclyl” is an aromatic (also referred to as heteroaryl) ornon-aromatic cycloalkyl in which one to four of the ring carbon atomsare independently replaced with a heteroatom from the group consistingof O, S and N. In some embodiments, heterocyclyl groups include 3 to 10ring members, whereas other such groups have 3 to 5, 3 to 6, or 3 to 8ring members. Heterocyclyls can also be bonded to other groups at anyring atom (i.e., at any carbon atom or heteroatom of the heterocyclicring). A heterocyclylalkyl group can be substituted or unsubstituted.Heterocyclyl groups encompass unsaturated, partially saturated andsaturated ring systems, such as, for example, imidazolyl, imidazolinyland imidazolidinyl groups. The phrase heterocyclyl includes fused ringspecies, including those comprising fused aromatic and non-aromaticgroups, such as, for example, benzotriazolyl,2,3-dihydrobenzo[1,4]dioxinyl, and benzo[1,3]dioxolyl. The phrase alsoincludes bridged polycyclic ring systems containing a heteroatom suchas, but not limited to, quinuclidyl. Representative examples of aheterocyclyl group include, but are not limited to, aziridinyl,azetidinyl, pyrrolidyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl,tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl, furanyl, thiophenyl,pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl,triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiazolinyl,isothiazolyl, thiadiazolyl, oxadiazolyl, piperidyl, piperazinyl,morpholinyl, thiomorpholinyl, tetrahydropyranyl (for example,tetrahydro-2H-pyranyl), tetrahydrothiopyranyl, oxathiane, dioxyl,dithianyl, pyranyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl,triazinyl, dihydropyridyl, dihydrodithiinyl, dihydrodithionyl,homopiperazinyl, quinuclidyl, indolyl, indolinyl, isoindolyl, azaindolyl(pyrrolopyridyl), indazolyl, indolizinyl, benzotriazolyl,benzimidazolyl, benzofuranyl, benzothiophenyl, benzthiazolyl,benzoxadiazolyl, benzoxazinyl, benzodithiinyl, benzoxathiinyl,benzothiazinyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl,benzo[1,3]dioxolyl, pyrazolopyridyl, imidazopyridyl (azabenzimidazolyl;for example, 1H-imidazo[4,5-b]pyridyl, or1H-imidazo[4,5-b]pyridin-2(3H)-onyl), triazolopyridyl, isoxazolopyridyl,purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl,quinolizinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl,naphthyridinyl, pteridinyl, thianaphthalenyl, dihydrobenzothiazinyl,dihydrobenzofuranyl, dihydroindolyl, dihydrobenzodioxinyl,tetrahydroindolyl, tetrahydroindazolyl, tetrahydrobenzimidazolyl,tetrahydrobenzotriazolyl, tetrahydropyrrolopyridyl,tetrahydropyrazolopyridyl, tetrahydroimidazopyridyl,tetrahydrotriazolopyridyl, and tetrahydroquinolinyl groups.Representative substituted heterocyclyl groups may be mono-substitutedor substituted more than once, such as, but not limited to, pyridyl ormorpholinyl groups, which are 2-, 3-, 4-, 5-, or 6-substituted, ordisubstituted with various substituents such as those listed below.

A “cycloalkylalkyl” group is a radical of the formula:-alkyl-cycloalkyl, wherein alkyl and cycloalkyl are defined above.Substituted cycloalkylalkyl groups may be substituted at the alkyl, thecycloalkyl, or both the alkyl and the cycloalkyl portions of the group.Representative cycloalkylalkyl groups include but are not limited tocyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl,and cyclohexylpropyl. Representative substituted cycloalkylalkyl groupsmay be mono-substituted or substituted more than once.

An “aralkyl” group is a radical of the formula: -alkyl-aryl, whereinalkyl and aryl are defined above. Substituted aralkyl groups may besubstituted at the alkyl, the aryl, or both the alkyl and the arylportions of the group. Representative aralkyl groups include but are notlimited to benzyl and phenethyl groups and fused (cycloalkylaryl)alkylgroups such as 4-ethyl-indanyl.

A “heterocyclylalkyl” group is a radical of the formula:-alkyl-heterocyclyl, wherein alkyl and heterocyclyl are defined above.Substituted heterocyclylalkyl groups may be substituted at the alkyl,the heterocyclyl, or both the alkyl and the heterocyclyl portions of thegroup. Representative heterocylylalkyl groups include but are notlimited to 4-ethyl-morpholinyl, 4-propylmorpholinyl, furan-2-yl methyl,furan-3-yl methyl, pyrdine-3-yl methyl,(tetrahydro-2H-pyran-4-yl)methyl, (tetrahydro-2H-pyran-4-yl)ethyl,tetrahydrofuran-2-yl methyl, tetrahydrofuran-2-yl ethyl, and indol-2-ylpropyl.

A “halogen” is chloro, iodo, bromo, or fluoro.

A “hydroxyalkyl” group is an alkyl group as described above substitutedwith one or more hydroxy groups.

An “alkoxy” group is —O-(alkyl), wherein alkyl is defined above.

An “alkoxyalkyl” group is -(alkyl)-O-(alkyl), wherein alkyl is definedabove.

An “amine” group is a radical of the formula: —NH₂.

A “hydroxylamine” group is a radical of the formula: —N(R^(#))OH or—NHOH, wherein R^(#) is a substituted or unsubstituted alkyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl orheterocyclylalkyl group as defined herein.

An “alkoxyamine” group is a radical of the formula: —N(R^(#))O-alkyl or—NHO-alkyl, wherein R^(#) is as defined above.

An “aralkoxyamine” group is a radical of the formula: —N(R^(#))O-aryl or—NHO-aryl, wherein R^(#) is as defined above.

An “alkylamine” group is a radical of the formula: —NH-alkyl or—N(alkyl)₂, wherein each alkyl is independently as defined above.

An “aminocarbonyl” group is a radical of the formula: —C(═O)N(R^(#))₂,—C(═O)NH(R^(#)) or —C(═O)NH₂, wherein each R^(#) is as defined above.

An “acylamino” group is a radical of the formula: —NHC(═O)(R^(#)) or—N(alkyl)C(═O)(R^(#)), wherein each alkyl and R^(#) are independently asdefined above.

An “O(alkyl)aminocarbonyl” group is a radical of the formula:—O(alkyl)C(═O)N(R^(#))₂, —O(alkyl)C(═O)NH(R^(#)) or —O(alkyl)C(═O)NH₂,wherein each R^(#) is independently as defined above.

An “N-oxide” group is a radical of the formula: —N⁺—O⁻.

A “carboxy” group is a radical of the formula: —C(═O)OH.

A “ketone” group is a radical of the formula: —C(═O)(R^(#)), whereinR^(#) is as defined above.

An “aldehyde” group is a radical of the formula: —CH(═O).

An “ester” group is a radical of the formula: —C(═O)O(R^(#)) or—OC(═O)(R^(#)), wherein R^(#) is as defined above.

A “urea” group is a radical of the formula: —N(alkyl)C(═O)N(R^(#))₂,—N(alkyl)C(═O)NH(R^(#)), —N(alkyl)C(═O)NH₂, —NHC(═O)N(R^(#))₂,—NHC(═O)NH(R^(#)), or —NHC(═O)NH₂ ^(#), wherein each alkyl and R^(#) areindependently as defined above.

An “imine” group is a radical of the formula: —N═C(R^(#))₂ or—C(R^(#))═N(R^(#)), wherein each R^(#) is independently as definedabove.

An “imide” group is a radical of the formula: —C(═O)N(R#)C(═O)(R#) or—N(C═O)(R^(#)))₂, wherein each R^(#) is independently as defined above.

A “urethane” group is a radical of the formula: —OC(═O)N(R^(#))₂,—OC(═O)NH(R^(#)), —N(R^(#))C(═O)O(R^(#)), or —NHC(═O)O(R^(#)), whereineach R^(#) is independently as defined above.

An “amidine” group is a radical of the formula: —C(═N(R^(#)))N(R^(#))₂,—C(═N(R^(#)))NH(R^(#)), —C(═N(R^(#)))NH₂, —C(═NH)N(R^(#))₂,—C(═NH)NH(R^(#)), —C(═NH)NH₂, —N═C(R^(#))N(R^(#))₂,—N═C(R^(#))NH(R^(#)), —N═C(R^(#))NH₂, —N(R^(#))C(R^(#))═N(R^(#)),—NHC(R^(#))═N(R^(#)), —N(R^(#))C(R^(#))═NH, or —NHC(R^(#))═NH, whereineach R^(#) is independently as defined above.

A “guanidine” group is a radical of the formula:—N(R^(#))C(═N(R^(#)))N(R^(#))₂, —NHC(═N(R^(#)))N(R^(#))₂,—N(R^(#))C(═NH)N(R^(#))₂, —N(R^(#))C(═N(R^(#)))NH(R^(#)),—N(R^(#))C(═N(R^(#)))NH₂, —NHC(═NH)N(R^(#))₂, —NHC(═N(R^(#)))NH(R^(#)),—NHC(═N(R^(#)))NH₂, —NHC(═NH)NH(R^(#)), —NHC(═NH)NH₂, —N═C(N(R^(#))₂)₂,—N═C(NH(R^(#)))₂, or —N═C(NH₂)₂, wherein each R^(#) is independently asdefined above.

A “enamine” group is a radical of the formula:—N(R^(#))C(R^(#))═C(R^(#))₂, —NHC(R^(#))═C(R^(#))₂,—C(N(R^(#))₂)═C(R^(#))₂, —C(NH(R^(#)))═C(R^(#))₂, —C(NH₂)═C(R^(#))₂,—C(R^(#))═C(R^(#))(N(R^(#))₂), —C(R^(#))═C(R^(#))(NH(R^(#))) or—C(R^(#))═C(R^(#))(NH₂), wherein each R^(#) is independently as definedabove.

An “oxime” group is a radical of the formula: —C(═NO(R^(#)))(R^(#)),—C(═NOH)(R^(#)), —CH(═NO(R^(#))), or —CH(═NOH), wherein each R^(#) isindependently as defined above.

A “hydrazide” group is a radical of the formula:—C(═O)N(R^(#))N(R^(#))₂, —C(═O)NHN(R^(#))₂, —C(═O)N(R^(#))NH(R^(#)),—C(═O)N(R^(#))NH₂, —C(═O)NHNH(R^(#))₂, or —C(═O)NHNH₂, wherein eachR^(#) is independently as defined above.

A “hydrazine” group is a radical of the formula: —N(R^(#))N(R^(#))₂,—NHN(R^(#))₂, —N(R^(#))NH(R^(#)), —N(R^(#))NH₂, —NHNH(R^(#))₂, or—NHNH₂, wherein each R^(#) is independently as defined above.

A “hydrazone” group is a radical of the formula:—C(═N—N(R^(#))₂)(R^(#))₂, —C(═N—NH(R^(#)))(R^(#))₂, —C(═N—NH₂)(R^(#))₂,—N(R^(#))(N═C(R^(#))₂), or —NH(N═C(R^(#))₂), wherein each R^(#) isindependently as defined above.

An “azide” group is a radical of the formula: —N₃.

An “isocyanate” group is a radical of the formula: —N═C═O.

An “isothiocyanate” group is a radical of the formula: —N═C═S.

A “cyanate” group is a radical of the formula: —OCN.

A “thiocyanate” group is a radical of the formula: —SCN.

A “thioether” group is a radical of the formula; —S(R^(#)), whereinR^(#) is as defined above.

A “thiocarbonyl” group is a radical of the formula: —C(═S)(R^(#)),wherein R^(#) is as defined above.

A “sulfinyl” group is a radical of the formula: —S(═O)(R^(#)), whereinR^(#) is as defined above.

A “sulfone” group is a radical of the formula: —S(═O)₂(R^(#)), whereinR^(#) is as defined above.

A “sulfonylamino” group is a radical of the formula: —NHSO₂(R^(#)) or—N(alkyl)SO₂(R^(#)), wherein each alkyl and R^(#) are defined above.

A “sulfonamide” group is a radical of the formula: —S(═O)₂N(R^(#))₂, or—S(═O)₂NH(R^(#)), or —S(═O)₂NH₂, wherein each R^(#) is independently asdefined above.

A “phosphonate” group is a radical of the formula: —P(═O)(O(R^(#)))₂,—P(═O)(OH)₂, —OP(═O)(O(R^(#)))(R^(#)), or —OP(═O)(OH)(R^(#)), whereineach R^(#) is independently as defined above.

A “phosphine” group is a radical of the formula: —P(R^(#))₂, whereineach R^(#) is independently as defined above.

When the groups described herein, with the exception of alkyl group aresaid to be “substituted,” they may be substituted with any appropriatesubstituent or substituents. Illustrative examples of substituents arethose found in the exemplary compounds and embodiments disclosed herein,as well as halogen (chloro, iodo, bromo, or fluoro); alkyl; hydroxyl;alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol;thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl;acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone;sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime;hydroxylamine; alkoxyamine; aralkoxyamine; N-oxide; hydrazine;hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate;thiocyanate; oxygen (═O); B(OH)₂, O(alkyl)aminocarbonyl; cycloalkyl,which may be monocyclic or fused or non-fused polycyclic (e.g.,cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), or a heterocyclyl,which may be monocyclic or fused or non-fused polycyclic (e.g.,pyrrolidyl, piperidyl, piperazinyl, morpholinyl, or thiazinyl);monocyclic or fused or non-fused polycyclic aryl or heteroaryl (e.g.,phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl,oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl,pyridinyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl,pyrimidinyl, benzimidazolyl, benzothiophenyl, or benzofuranyl) aryloxy;aralkyloxy; heterocyclyloxy; and heterocyclyl alkoxy.

As used herein, the term “pharmaceutically acceptable salt(s)” refers toa salt prepared from a pharmaceutically acceptable non-toxic acid orbase including an inorganic acid and base and an organic acid and base.Suitable pharmaceutically acceptable base addition salts include, butare not limited to metallic salts made from aluminum, calcium, lithium,magnesium, potassium, sodium and zinc or organic salts made from lysine,N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine (N-methylglucamine) and procaine. Suitablenon-toxic acids include, but are not limited to, inorganic and organicacids such as acetic, alginic, anthranilic, benzenesulfonic or besylate,benzoic, camphorsulfonic, citric, ethenesulfonic, formic, fumaric,furoic, galacturonic, gluconic, glucuronic, glutamic, glycolic,hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic,methanesulfonic, mucic, nitric, pamoic, pantothenic, phenylacetic,phosphoric, propionic, salicylic, stearic, succinic, sulfanilic,sulfuric, tartaric acid, and p-toluenesulfonic acid. Specific non-toxicacids include hydrochloric, hydrobromic, phosphoric, sulfuric, andmethanesulfonic acids. Examples of specific salts thus includehydrochloride and mesylate salts. Others are well-known in the art, seefor example, Remington's Pharmaceutical Sciences, 18^(th) eds., MackPublishing, Easton Pa. (1990) or Remington: The Science and Practice ofPharmacy, 19^(th) eds., Mack Publishing, Easton Pa. (1995).

As used herein and unless otherwise indicated, the term “clathrate”means a TOR kinase inhibitor, or a salt thereof, in the form of acrystal lattice that contains spaces (e.g., channels) that have a guestmolecule (e.g., a solvent or water) trapped within or a crystal latticewherein a TOR kinase inhibitor is a guest molecule.

As used herein and unless otherwise indicated, the term “solvate” meansa TOR kinase inhibitor, or a salt thereof, that further includes astoichiometric or non-stoichiometric amount of a solvent bound bynon-covalent intermolecular forces. In one embodiment, the solvate is ahydrate.

As used herein and unless otherwise indicated, the term “hydrate” meansa TOR kinase inhibitor, or a salt thereof, that further includes astoichiometric or non-stoichiometric amount of water bound bynon-covalent intermolecular forces.

As used herein and unless otherwise indicated, the term “prodrug” meansa TOR kinase inhibitor derivative that can hydrolyze, oxidize, orotherwise react under biological conditions (in vitro or in vivo) toprovide an active compound, particularly a TOR kinase inhibitor.Examples of prodrugs include, but are not limited to, derivatives andmetabolites of a TOR kinase inhibitor that include biohydrolyzablemoieties such as biohydrolyzable amides, biohydrolyzable esters,biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzableureides, and biohydrolyzable phosphate analogues. In certainembodiments, prodrugs of compounds with carboxyl functional groups arethe lower alkyl esters of the carboxylic acid. The carboxylate estersare conveniently formed by esterifying any of the carboxylic acidmoieties present on the molecule. Prodrugs can typically be preparedusing well-known methods, such as those described by Burger's MedicinalChemistry and Drug Discovery 6^(th) ed. (Donald J. Abraham ed., 2001,Wiley) and Design and Application of Prodrugs (H. Bundgaard ed., 1985,Harwood Academic Publishers Gmfh).

As used herein and unless otherwise indicated, the term “stereoisomer”or “stereomerically pure” means one stereoisomer of a TOR kinaseinhibitor that is substantially free of other stereoisomers of thatcompound. For example, a stereomerically pure compound having one chiralcenter will be substantially free of the opposite enantiomer of thecompound. A stereomerically pure compound having two chiral centers willbe substantially free of other diastereomers of the compound. A typicalstereomerically pure compound comprises greater than about 80% by weightof one stereoisomer of the compound and less than about 20% by weight ofother stereoisomers of the compound, greater than about 90% by weight ofone stereoisomer of the compound and less than about 10% by weight ofthe other stereoisomers of the compound, greater than about 95% byweight of one stereoisomer of the compound and less than about 5% byweight of the other stereoisomers of the compound, or greater than about97% by weight of one stereoisomer of the compound and less than about 3%by weight of the other stereoisomers of the compound. The TOR kinaseinhibitors can have chiral centers and can occur as racemates,individual enantiomers or diastereomers, and mixtures thereof. All suchisomeric forms are included within the embodiments disclosed herein,including mixtures thereof. The use of stereomerically pure forms ofsuch TOR kinase inhibitors, as well as the use of mixtures of thoseforms are encompassed by the embodiments disclosed herein. For example,mixtures comprising equal or unequal amounts of the enantiomers of aparticular TOR kinase inhibitor may be used in methods and compositionsdisclosed herein. These isomers may be asymmetrically synthesized orresolved using standard techniques such as chiral columns or chiralresolving agents. See, e.g., Jacques, J., et al., Enantiomers, Racematesand Resolutions (Wiley-Interscience, New York, 1981); Wilen, S. H., etal., Tetrahedron 33:2725 (1977); Eliel, E. L., Stereochemistry of CarbonCompounds (McGraw-Hill, NY, 1962); and Wilen, S. H., Tables of ResolvingAgents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of NotreDame Press, Notre Dame, Ind., 1972).

It should also be noted the TOR kinase inhibitors can include E and Zisomers, or a mixture thereof, and cis and trans isomers or a mixturethereof. In certain embodiments, the TOR kinase inhibitors are isolatedas either the cis or trans isomer. In other embodiments, the TOR kinaseinhibitors are a mixture of the cis and trans isomers.

“Tautomers” refers to isomeric forms of a compound that are inequilibrium with each other. The concentrations of the isomeric formswill depend on the environment the compound is found in and may bedifferent depending upon, for example, whether the compound is a solidor is in an organic or aqueous solution. For example, in aqueoussolution, pyrazoles may exhibit the following isomeric forms, which arereferred to as tautomers of each other:

As readily understood by one skilled in the art, a wide variety offunctional groups and other structures may exhibit tautomerism and alltautomers of the TOR kinase inhibitors are within the scope of thepresent invention.

It should also be noted the TOR kinase inhibitors can contain unnaturalproportions of atomic isotopes at one or more of the atoms. For example,the compounds may be radiolabeled with radioactive isotopes, such as forexample tritium (³H), iodine-125 (¹²⁵I), sulfur-35 (³⁵S), or carbon-14(¹⁴C), or may be isotopically enriched, such as with deuterium (²H),carbon-13 (¹³C), or nitrogen-15 (¹⁵N). As used herein, an “isotopologue”is an isotopically enriched compound. The term “isotopically enriched”refers to an atom having an isotopic composition other than the naturalisotopic composition of that atom. “Isotopically enriched” may alsorefer to a compound containing at least one atom having an isotopiccomposition other than the natural isotopic composition of that atom.The term “isotopic composition” refers to the amount of each isotopepresent for a given atom. Radiolabeled and isotopically enrichedcompounds are useful as therapeutic agents, e.g., cancer andinflammation therapeutic agents, research reagents, e.g., binding assayreagents, and diagnostic agents, e.g., in vivo imaging agents. Allisotopic variations of the TOR kinase inhibitors as described herein,whether radioactive or not, are intended to be encompassed within thescope of the embodiments provided herein. In some embodiments, there areprovided isotopologues of the TOR kinase inhibitors, for example, theisotopologues are deuterium, carbon-13, or nitrogen-15 enriched TORkinase inhibitors.

It should be noted that if there is a discrepancy between a depictedstructure and a name for that structure, the depicted structure is to beaccorded more weight.

“Treating” as used herein, means an alleviation, in whole or in part, ofa cancer or a symptom associated with a cancer, or slowing, or haltingof further progression or worsening of those symptoms.

“Preventing” as used herein, means the prevention of the onset,recurrence or spread, in whole or in part, of a cancer, or a symptomthereof.

The term “effective amount” in connection with an TOR kinase inhibitoror Compound AA means an amount alone or in combination capable ofalleviating, in whole or in part, a symptom associated with a cancer, orslowing or halting further progression or worsening of those symptoms,or treating or preventing a cancer in a subject having or at risk forhaving a cancer. The effective amount of the TOR kinase inhibitor orCompound AA, for example in a pharmaceutical composition, may be at alevel that will exercise the desired effect; for example, about 0.005mg/kg of a subject's body weight to about 100 mg/kg of a patient's bodyweight in unit dosage for both oral and parenteral administration.

The term “cancer” includes, but is not limited to, blood born tumors andsolid tumors. Blood born tumors include lymphomas, leukemias andmyelomas. Lymphomas and leukemias are malignancies arising among whiteblood cells. The term “cancer” also refers to any of various malignantneoplasms characterized by the proliferation of cells that can invadesurrounding tissue and metastasize to new body sites. Both benign andmalignant tumors are classified according to the type of tissue in whichthey are found. For example, fibromas are neoplasms of fibrousconnective tissue, and melanomas are abnormal growths of pigment(melanin) cells. Malignant tumors originating from epithelial tissue,e.g., in skin, bronchi, and stomach, are termed carcinomas. Malignanciesof epithelial glandular tissue such as are found in the breast,prostate, and colon, are known as adenocarcinomas. Malignant growths ofconnective tissue, e.g., muscle, cartilage, lymph tissue, and bone, arecalled sarcomas. Through the process of metastasis, tumor cell migrationto other areas of the body establishes neoplasms in areas away from thesite of initial appearance. Bone tissues are one of the most favoredsites of metastases of malignant tumors, occurring in about 30% of allcancer cases. Among malignant tumors, cancers of the lung, breast,prostate or the like are particularly known to be likely to metastasizeto bone.

In the context of neoplasm, cancer, tumor growth or tumor cell growth,inhibition may be assessed by delayed appearance of primary or secondarytumors, slowed development of primary or secondary tumors, decreasedoccurrence of primary or secondary tumors, slowed or decreased severityof secondary effects of disease, arrested tumor growth and regression oftumors, among others. In the extreme, complete inhibition, is referredto herein as prevention or chemoprevention. In this context, the term“prevention” includes either preventing the onset of clinically evidentneoplasia altogether or preventing the onset of a preclinically evidentstage of neoplasia in individuals at risk. Also intended to beencompassed by this definition is the prevention of transformation intomalignant cells or to arrest or reverse the progression of premalignantcells to malignant cells. This includes prophylactic treatment of thoseat risk of developing the neoplasia.

The term “refractory B-cell non-Hodgkin's lymphoma” as used herein isdefined as B-cell non-Hodgkin's lymphoma which was treated with ananti-CD-20 antibody-containing regimen, for example rituximab-containingregimen, (i) without achieving at least a partial response to therapy or(ii) which progressed within 6 months of treatment.

The term “relapsed B-cell non-Hodgkin's lymphoma” as used herein isdefined as B-cell non-Hodgkin's lymphoma which progressed after ≧6months post-treatment with an anti-CD-20 antibody-containing regimen,for example rituximab-containing regimen, after achieving partialresponse or complete response to therapy.

A person of ordinary skill will appreciate that diseases characterizedas “B-cell lymphoma” exist as a continuum of diseases or disorders.While the continuum of B-cell lymphomas is sometimes discussed in termsof “aggressive” B-cell lymphomas or “indolent” B-cell lymphomas, aperson of ordinary skill will appreciate that a B-cell lymphomacharacterized as indolent may progress and become an aggressive B-celllymphoma. Conversely, an aggressive form of B-cell lymphoma may bedowngraded to an indolent or stable form of B-cell lymphoma. Referenceis made to indolent and aggressive B-cell lymphomas as generallyunderstood by a person skilled in the art with the recognition that suchcharacterizations are inherently dynamic and depend on the particularcircumstances of the individual.

As used herein, and unless otherwise specified, the term “in combinationwith” includes the administration of two or more therapeutic agentssimultaneously, concurrently, or sequentially within no specific timelimits unless otherwise indicated. In one embodiment, a TOR kinaseinhibitor is administered in combination with Compound AA. In oneembodiment, a TOR kinase inhibitor is administered in combination withCompound AA and further in combination with an anti-CD20 antibody, forexample, rituximab (Rituxan®, Biogen Idec/Genentech or MabThera®,Hoffmann-La Roche). In one embodiment, the agents are present in thecell or in the subject's body at the same time or exert their biologicalor therapeutic effect at the same time. In one embodiment, thetherapeutic agents are in the same composition or unit dosage form. Inother embodiments, the therapeutic agents are in separate compositionsor unit dosage forms. In certain embodiments, a first agent can beadministered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6weeks, 8 weeks, or 12 weeks before), essentially concomitantly with, orsubsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours,96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks,or 12 weeks after) the administration of a second therapeutic agent, orany combination thereof. For example, in one embodiment, the first agentcan be administered prior to the second therapeutic agent, for e.g. 1week. In another, the first agent can be administered prior to (forexample 1 day prior) and then concomitant with the second therapeuticagent.

The terms “patient” and “subject” as used herein include an animal,including, but not limited to, an animal such as a cow, monkey, horse,sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit orguinea pig, in one embodiment a mammal, in another embodiment a human.In one embodiment, a “patient” or “subject” is a human having a cancer.

In the context of a cancer, inhibition may be assessed by inhibition ofdisease progression, inhibition of tumor growth, reduction of primarytumor, relief of tumor-related symptoms, inhibition of tumor secretedfactors (including tumor secreted hormones, such as those thatcontribute to carcinoid syndrome), delayed appearance of primary orsecondary tumors, slowed development of primary or secondary tumors,decreased occurrence of primary or secondary tumors, slowed or decreasedseverity of secondary effects of disease, arrested tumor growth andregression of tumors, increased Time To Progression (TTP), increasedProgression Free Survival (PFS), increased Overall Survival (OS), amongothers. OS as used herein means the time from randomization until deathfrom any cause, and is measured in the intent-to-treat population. TTPas used herein means the time from randomization until objective tumorprogression; TTP does not include deaths. As used herein, PFS means thetime from randomization until objective tumor progression or death. Inone embodiment, PFS rates will be computed using the Kaplan-Meierestimates. In the extreme, complete inhibition, is referred to herein asprevention or chemoprevention. In this context, the term “prevention”includes either preventing the onset of clinically evident canceraltogether or preventing the onset of a preclinically evident stage of acancer. Also intended to be encompassed by this definition is theprevention of transformation into malignant cells or to arrest orreverse the progression of premalignant cells to malignant cells. Thisincludes prophylactic treatment of those at risk of developing a cancer.

In certain embodiments, the treatment of lymphoma may be assessed by theInternational Workshop Criteria (IWC) for non-Hodgkin lymphoma (NHL)(see Cheson B D, Pfistner B, Juweid, M E, et. al. Revised ResponseCriteria for Malignant Lymphoma. J. Clin. Oncol: 2007: (25) 579-586),using the response and endpoint definitions shown below:

Response Definition Nodal Masses Spleen, liver Bone Marrow CRDisappearance (a) FDG-avid or PET positive Not palpable, Infiltratecleared of all evidence prior to therapy; mass of any nodules on repeatbiopsy; if of disease size permitted if PET disappeared indeterminate bynegative morphology, (b) Variably FDG-avid or immunohistochemistry PETnegative; regression should be negative to normal size on CT PRRegression of ≧50% decrease in SPD of up to ≧50% decrease in Irrelevantif measurable 6 largest dominant masses; no SPD of nodules (for positiveprior to disease and increase in size of other nodes single nodule intherapy; cell type no new sites (a) FDG-avid or PET positive greatesttransverse should be specified prior to therapy; one or more diameter);no increase PET positive at previously in size of liver or involved sitespleen (b) Variably FDG-avid or PET negative; regression on CT SDFailure to attain (a) FDG-avid or PET positive CR/PR or PD prior totherapy; PET positive at prior sites of disease and no new sites on CTor PET (b) Variably FDG-avid or PET negative; no change in size ofprevious lesions on CT PD or Any new lesion or Appearance of a newlesion(s) ≧1.5 ≧50% increase from New or recurrent relapsed increase by≧50% cm in any axis, ≧50% increase in nadir in the SPD of involvementdisease of previously SPD of more than one node, or ≧50% any previouslesions involved sites increase in longest diameter of from nadir apreviously identifed node ≧1 cm in short axis Lesions PET positive ifFDG-avid lymphoma or PET positive prior to therapy Abbreviations: CR,complete remission; FDG, [¹⁸F]fluorodeoxyglucose; PET, positron emissiontomography; CT, computed tomography; PR, partial remission; SPD, sum ofthe product of the diameters; SD, stable disease; PD, progressivedisease.

End point Patients Definition Measured from Primary Overall survival AllDeath as a result of any cause Entry onto study Progression-free AllDisease progression or death as a result of Entry onto study survivalany cause Secondary Event-free survival All Failure of treatment ordeath as result of any Entry onto study cause Time to All Time toprogression or death as a result of Entry onto study progressionlymphoma Disease-free In CR Time to relapse or death as a result ofDocumentation survival lymphoma or acute toxicity of treatment ofresponse Response duration In CR or Time to relapse or progressionDocumentation PR of response Lymphoma- All Time to death as a result oflymphoma Entry onto study specific survival Time to next All Time to newtreatment End of primary treatment treatment Abbreviations: CR: completeremission; PR: partial remission.

In one embodiment, the end point for lymphoma is evidence of clinicalbenefit. Clinical benefit may reflect improvement in quality of life, orreduction in patient symptoms, transfusion requirements, frequentinfections, or other parameters. Time to reappearance or progression oflymphoma-related symptoms can also be used in this end point.

In certain embodiments, the treatment of CLL may be assessed by theInternational Workshop Guidelines for CLL (see Hallek M, Cheson B D,Catovsky D, et al. Guidelines for the diagnosis and treatment of chroniclymphocytic leukemia: a report from the International Workshop onChronic Lymphocytic Leukemia updating the National CancerInstitute-Working Group 1996 guidelines. Blood, 2008; (111) 12:5446-5456) using the response and endpoint definitions shown therein andin particular:

Parameter CR PR PD Group A Lymphadenopathy^(†) None > 1.5 cm Decrease ≧50% Increase ≧ 50% Hepatomegaly None Decrease ≧ 50% Increase ≧ 50%Splenomegaly None Decrease ≧ 50% Increase ≧ 50% Blood lymphocytes<4000/μL Decrease ≧ 50% Increase ≧ 50% from baseline over baselineMarrow‡ Normocellular, <30% 50% reduction in lymphocytes, no B-lymphoidmarrow infiltrate, or nodules. Hypocellular marrow B-lymphoid nodulesdefines CRi (5.1.6). Group B Platelet count >100 000/μL >100 000/μL orDecrease of ≧50% increase ≧ 50% over from baseline baseline secondary toCLL Hemoglobin >11.0 g/dL >11 g/dL or increase Decrease of > 2 g/dL ≧50%over baseline from baseline secondary to CLLNeutrophils^(‡) >1500/μL >1500/μL or >50% improvement over baselineGroup A criteria define the tumor load; Group B criteria define thefunction of the hematopoietic system (or marrow). CR (completeremission): all of the criteria have to be met, and patients have tolack disease-related constitutional symptoms; PR (partial remission): atleast two of the criteria of group A plus one of the criteria of group Bhave to be met; SD is absence of progressive disease (PD) and failure toachieve at least a PR; PD: at least one of the above criteria of group Aor group B has to be met. Sum of the products of multiple lymph nodes(as evaluated by CT scans in clinical trials, or by physical examinationin general practice). These parameters are irrelevant for some responsecategories.

In certain embodiments, the treatment of multiple myeloma may beassessed by the International Uniform Response Criteria for MultipleMyeloma (IURC) (see Durie B G M, Harousseau J-L, Miguel J S, et al.International uniform response criteria for multiple myeloma. Leukemia,2006; (10) 10:1-7), using the response and endpoint definitions shownbelow:

Response Subcategory Response Criteria^(a) sCR CR as defined below plusNormal FLC ratio and Absence of clonal cells in bone marrow^(b) byimmunohistochemistry or immunofluorescence^(c) CR Negativeimmunofixation on the serum and urine and Disappearance of any softtissue plasmacytomas and < 5% plasma cells in bone marrow^(b) VGPR Serumand urine M-protein detectable by immunofixation but not onelectrophoresis or 90% or greater reduction in serum M-protein plusurine M-protein level < 100 mg per 24 h PR ≧50% reduction of serumM-protein and reduction in 24-h urinary M-protein by ≧ 90% or to < 200mg per 24 h If the serum and urine M-protein are unmeasurable,^(d) a≧50% decrease in the difference between involved and uninvolved FLClevels is required in place of the M- protein criteria If serum andurine M-protein are unmeasurable, and serum free light assay is alsounmeasurable, ≧50% reduction in plasma cells is required in place ofM-protein, provided baseline bone marrow plasma cell percentage was ≧30% In addition to the above listed criteria, if present at baseline, a≧ 50% reduction in the size of soft tissue plasmacytomas is alsorequired SD (not recommended for use as an Not meeting criteria for CR,VGPR, PR or progressive indicator of response; stability of diseasedisease is best described by providing the time to progressionestimates) Abbreviations: CR, complete response; FLC, free light chain;PR, partial response; SD, stable disease; sCR, stringent completeresponse; VGPR, very good partial response; ^(a)All response categoriesrequire two consecutive assessments made at anytime before theinstitution of any new therapy; all categories also require no knownevidence of progressive or new bone lesions if radiographic studies wereperformed. Radiographic studies are not required to satisfy theseresponse requirements; ^(b)Confirmation with repeat bone marrow biopsynot needed; ^(c)Presence/absence of clonal cells is based upon the κ/λratio. An abnormal κ/λ ratio by immunohistochemistry and/orimmunofluorescence requires a minimum of 100 plasma cells for analysis.An abnormal ratio reflecting presence of an abnormal clone is κ/λ of >4:1 or < 1:2. ^(d)Measurable disease defined by at least one of thefollowing measurements: Bone marrow plasma cells ≧ 30%; Serum M-protein≧ 1 g/dl (≧10 gm/l)[10 g/l]; Urine M-protein ≧ 200 mg/24 h; Serum FLCassay: Involved FLC level ≧ 10 mg/dl (≧100 mg/l); provided serum FLCratio is abnormal.

In certain embodiments, the treatment of a cancer may be assessed byResponse Evaluation Criteria in Solid Tumors (RECIST 1.1) (see ThereasseP., et al. New Guidelines to Evaluate the Response to Treatment in SolidTumors. J. of the National Cancer Institute; 2000; (92) 205-216 andEisenhauer E. A., Therasse P., Bogaerts J., et al. New responseevaluation criteria in solid tumours: Revised RECIST guideline (version1.1). European J. Cancer; 2009; (45) 228-247). Overall responses for allpossible combinations of tumor responses in target and non-targetlesions with our without the appearance of new lesions are as follows:

Target lesions Non-target lesions New lesions Overall response CR CR NoCR CR Incomplete No PR response/SD PR Non-PD No PR SD Non-PD No SD PDAny Yes or no PD Any PD Yes or no PD Any Any Yes PD CR = completeresponse; PR = partial response; SD = stable disease; and PD =progressive disease.

With respect to the evaluation of target lesions, complete response (CR)is the disappearance of all target lesions, partial response (PR) is atleast a 30% decrease in the sum of the longest diameter of targetlesions, taking as reference the baseline sum longest diameter,progressive disease (PD) is at least a 20% increase in the sum of thelongest diameter of target lesions, taking as reference the smallest sumlongest diameter recorded since the treatment started or the appearanceof one or more new lesions and stable disease (SD) is neither sufficientshrinkage to qualify for partial response nor sufficient increase toqualify for progressive disease, taking as reference the smallest sumlongest diameter since the treatment started.

With respect to the evaluation of non-target lesions, complete response(CR) is the disappearance of all non-target lesions and normalization oftumor marker level; incomplete response/stable disease (SD) is thepersistence of one or more non-target lesion(s) and/or the maintenanceof tumor marker level above the normal limits, and progressive disease(PD) is the appearance of one or more new lesions and/or unequivocalprogression of existing non-target lesions.

The procedures, conventions, and definitions described below provideguidance for implementing the recommendations from the ResponseAssessment for Neuro-Oncology (RANO) Working Group regarding responsecriteria for high-grade gliomas (Wen P., Macdonald, D R., Reardon, D A.,et al. Updated response assessment criteria for highgrade gliomas:Response assessment in neuro-oncology working group. J Clin Oncol 2010;28: 1963-1972). Primary modifications to the RANO criteria for Criteriafor Time Point Responses (TPR) can include the addition of operationalconventions for defining changes in glucocorticoid dose, and the removalof subjects' clinical deterioration component to focus on objectiveradiologic assessments. The baseline MRI scan is defined as theassessment performed at the end of the post-surgery rest period, priorto re-initiating compound treatment. The baseline MRI is used as thereference for assessing complete response (CR) and partial response(PR). Whereas, the smallest SPD (sum of the products of perpendiculardiameters) obtained either at baseline or at subsequent assessments willbe designated the nadir assessment and utilized as the reference fordetermining progression. For the 5 days preceding any protocol-definedMRI scan, subjects receive either no glucocorticoids or are on a stabledose of glucocorticoids. A stable dose is defined as the same daily dosefor the 5 consecutive days preceding the MRI scan. If the prescribedglucocorticoid dose is changed in the 5 days before the baseline scan, anew baseline scan is required with glucocorticoid use meeting thecriteria described above. The following definitions will be used.

Measurable Lesions: Measurable lesions are contrast-enhancing lesionsthat can be measured bidimensionally. A measurement is made of themaximal enhancing tumor diameter (also known as the longest diameter,LD). The greatest perpendicular diameter is measured on the same image.The cross hairs of bidimensional measurements should cross and theproduct of these diameters will be calculated.

Minimal Diameter: T1-weighted image in which the sections are 5 mm with1 mm skip. The minimal LD of a measurable lesion is set as 5 mm by 5 mm.Larger diameters may be required for inclusion and/or designation astarget lesions. After baseline, target lesions that become smaller thanthe minimum requirement for measurement or become no longer amenable tobidimensional measurement will be recorded at the default value of 5 mmfor each diameter below 5 mm. Lesions that disappear will be recorded as0 mm by 0 mm.

Multicentric Lesions: Lesions that are considered multicentric (asopposed to continuous) are lesions where there is normal interveningbrain tissue between the two (or more) lesions. For multicentric lesionsthat are discrete foci of enhancement, the approach is to separatelymeasure each enhancing lesion that meets the inclusion criteria. Ifthere is no normal brain tissue between two (or more) lesions, they willbe considered the same lesion.

Nonmeasurable Lesions: All lesions that do not meet the criteria formeasurable disease as defined above will be considered non-measurablelesions, as well as all nonenhancing and other truly nonmeasurablelesions. Nonmeasurable lesions include foci of enhancement that are lessthan the specified smallest diameter (ie., less than 5 mm by 5 mm),nonenhancing lesions (eg., as seen on T1-weighted post-contrast,T2-weighted, or fluid-attenuated inversion recovery (FLAIR) images),hemorrhagic or predominantly cystic or necrotic lesions, andleptomeningeal tumor. Hemorrhagic lesions often have intrinsicT1-weighted hyperintensity that could be misinterpreted as enhancingtumor, and for this reason, the pre-contrast T1-weighted image may beexamined to exclude baseline or interval sub-acute hemorrhage.

At baseline, lesions will be classified as follows: Target lesions: Upto 5 measurable lesions can be selected as target lesions with eachmeasuring at least 10 mm by 5 mm, representative of the subject'sdisease; Non-target lesions: All other lesions, including allnonmeasurable lesions (including mass effects and T2/FLAIR findings) andany measurable lesion not selected as a target lesion. At baseline,target lesions are to be measured as described in the definition formeasurable lesions and the SPD of all target lesions is to bedetermined. The presence of all other lesions is to be documented. Atall post-treatment evaluations, the baseline classification of lesionsas target and non-target lesions will be maintained and lesions will bedocumented and described in a consistent fashion over time (eg.,recorded in the same order on source documents and eCRFs). Allmeasurable and nonmeasurable lesions must be assessed using the sametechnique as at baseline (e.g., subjects should be imaged on the sameMRI scanner or at least with the same magnet strength) for the durationof the study to reduce difficulties in interpreting changes. At eachevaluation, target lesions will be measured and the SPD calculated.Non-target lesions will be assessed qualitatively and new lesions, ifany, will be documented separately. At each evaluation, a time pointresponse will be determined for target lesions, non-target lesions, andnew lesion. Tumor progression can be established even if only a subsetof lesions is assessed. However, unless progression is observed,objective status (stable disease, PR or CR) can only be determined whenall lesions are assessed.

Confirmation assessments for overall time point responses of CR and PRwill be performed at the next scheduled assessment, but confirmation maynot occur if scans have an interval of <28 days. Best response,incorporating confirmation requirements, will be derived from the seriesof time points.

In certain embodiments, treatment of a cancer may be assessed by theinhibition of phosphorylation of S6RP, 4E-BP1, AKT and/or DNA-PK incirculating blood and/or tumor cells, and/or skin biopsies or tumorbiopsies/aspirates, before, during and/or after treatment with a TORkinase inhibitor. For example, the inhibition of phosphorylation ofS6RP, 4E-BP1, AKT and/or DNA-PK is assessed in B-cells, T-cells and/ormonocytes. In other embodiments, treatment of a cancer may be assessedby the inhibition of DNA-dependent protein kinase (DNA-PK) activity inskin samples and/or tumor biopsies/aspirates, such as by assessment ofthe amount of pDNA-PK S2056 as a biomarker for DNA damage pathways,before, during, and/or after TOR kinase inhibitor treatment. In oneembodiment, the skin sample is irradiated by UV light.

In the extreme, complete inhibition, is referred to herein as preventionor chemoprevention. In this context, the term “prevention” includeseither preventing the onset of clinically evident cancer altogether orpreventing the onset of a preclinically evident stage of a cancer. Alsointended to be encompassed by this definition is the prevention oftransformation into malignant cells or to arrest or reverse theprogression of premalignant cells to malignant cells. This includesprophylactic treatment of those at risk of developing a cancer.

As used herein, the term “antibody”, or grammatical variations thereof(i.e., antibodies), refers to polypeptide(s) capable of binding to anepitope. In some embodiments, an antibody is a full-length antibody. Insome embodiments, an antibody is less than full length (i.e., anantibody fragment) but includes at least one binding site. In some suchembodiments, the binding site comprises at least one, and preferably atleast two sequences with structure of antibody variable regions. In someembodiments, the term “antibody” encompasses any protein having abinding domain which is homologous or largely homologous to animmunoglobulin-binding domain. In particular embodiments, the term“antibody” encompasses polypeptides having a binding domain that showsat least 99% identity with an immunoglobulin-binding domain. In someembodiments, the antibody is any protein having a binding domain thatshows at least 70%, at least 80%, at least 85%, at least 90% or at least95% identity with an immunoglobulin-binding domain. Antibodypolypeptides in accordance with the present invention may be prepared byany available means, including, for example, isolation from a naturalsource or antibody library, recombinant production in or with a hostsystem, chemical synthesis, etc., or combinations thereof. In someembodiments, an antibody is monoclonal or polyclonal. In someembodiments, an antibody may be a member of any immunoglobulin class,including any of the human classes IgG, IgM, IgA, IgD and IgE. Incertain embodiments, an antibody is a member of the IgG immunoglobulinclass. In some embodiments, the term “antibody” refers to any derivativeof an antibody that possesses the ability to bind to an epitope ofinterest. In some embodiments, an antibody fragment comprises multiplechains that are linked together, for example, by disulfide linkages. Insome embodiments, an antibody is a human antibody. In some embodiments,an antibody is a humanized antibody. In some embodiments, humanizedantibodies include chimeric immunoglobulins, immunoglobulin chains orantibody fragments (Fv, Fab, Fab′, F(ab′)₂ or other antigen bindingsubsequences of antibodies) that contain minimal sequence derived fromnon-human immunoglobulin. In some embodiments, humanized antibodies arehuman immunoglobulin (recipient antibody) in which residues from acomplementary-determining region (CDR) of the recipient are replaced byresidues from a CDR of a non-human species (donor antibody) such asmouse, rat or rabbit having the desired specificity, affinity andcapacity. In particular embodiments, antibodies for use in the presentinvention bind to particular epitopes of CD20. In some embodiments,epitopes of CD20 to which anti-CD20 antibodies bind include, forexample, 170ANPS173 (Binder et al., Blood 2006, 108(6): 1975-1978), FMC7(Deans et al., Blood 2008, 111(4): 2492), Rp5-L and Rp15-C (mimotopes ofCD20) (Perosa et al., J. Immunol. 2009, 182:416-423), 182YCYSI185(Binder et al., Blood 2006, 108(6): 1975-1978) and WEWTI (a mimic of182YCYSI185) (Binder et al., Blood 2006, 108(6): 1975-1978). In someembodiments, an anti-CD20 antibody has a binding affinity (Kd) for anepitope of CD20 of less than 12 nM, less than 11 nM, less than 10 nM,less than 9 nM, less than 8 nM, less than 7 nM, less than 6 nM, lessthan 5 nM, less than 4 nM, less than 3 nM, less than 2 nM or less than 1nM.

As used herein, the term “biosimilar” (for example, of an approvedreference product/biological drug, such as a protein therapeutic,antibody, etc.) refers to a biologic product that is similar to thereference product based upon data derived from (a) analytical studiesthat demonstrate that the biological product is highly similar to thereference product notwithstanding minor differences in clinicallyinactive components; (b) animal studies (including the assessment oftoxicity); and/or (c) a clinical study or studies (including theassessment of immunogenicity and pharmacokinetics or pharmacodynamics)that are sufficient to demonstrate safety, purity, and potency in one ormore appropriate conditions of use for which the reference product isapproved and intended to be used and for which approval is sought (e.g.,that there are no clinically meaningful differences between thebiological product and the reference product in terms of the safety,purity, and potency of the product).

In some embodiments, the biosimilar biological product and referenceproduct utilizes the same mechanism or mechanisms of action for thecondition or conditions of use prescribed, recommended, or suggested inthe proposed labeling, but only to the extent the mechanism ormechanisms of action are known for the reference product. In someembodiments, the condition or conditions of use prescribed, recommended,or suggested in the labeling proposed for the biological product havebeen previously approved for the reference product. In some embodiments,the route of administration, the dosage form, and/or the strength of thebiological product are the same as those of the reference product. Insome embodiments, the facility in which the biological product ismanufactured, processed, packed, or held meets standards designed toassure that the biological product continues to be safe, pure, andpotent. The reference product may be approved in at least one of theU.S., Europe, or Japan. A biosimilar can be for example, a presentlyknown antibody having the same primary amino acid sequence as a marketedantibody, but may be made in different cell types or by differentproduction, purification or formulation methods.

5.2 TOR Kinase Inhibitors

The compounds provided herein are generally referred to as “TOR kinaseinhibitor(s).” In one aspect, the TOR kinase inhibitors do not includerapamycin or rapamycin analogs (rapalogs).

In one embodiment, the TOR kinase inhibitors include compounds havingthe following formula (I):

and pharmaceutically acceptable salts, clathrates, solvates,stereoisomers, tautomers, metabolites, isotopologues and prodrugsthereof, wherein:

R¹ is substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted aryl, substituted or unsubstituted cycloalkyl, substitutedor unsubstituted heterocyclyl, or substituted or unsubstitutedheterocyclylalkyl;

R² is H, substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted heterocyclylalkyl, substituted orunsubstituted aralkyl, or substituted or unsubstituted cycloalkylalkyl;

R³ is H, or a substituted or unsubstituted C₁₋₈ alkyl,

wherein in certain embodiments, the TOR kinase inhibitors do not include7-(4-hydroxyphenyl)-1-(3-methoxybenzyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one,depicted below:

In some embodiments of compounds of formula (I), R¹ is substituted orunsubstituted aryl or substituted or unsubstituted heteroaryl. Forexample, R¹ is phenyl, pyridyl, pyrimidyl, benzimidazolyl,1H-pyrrolo[2,3-b]pyridyl, indazolyl, indolyl, 1H-imidazo[4,5-b]pyridyl,1H-imidazo[4,5-b]pyridin-2(3H)-onyl, 3H-imidazo[4,5-b]pyridyl, orpyrazolyl, each optionally substituted. In some embodiments, R¹ isphenyl substituted with one or more substituents independently selectedfrom the group consisting of substituted or unsubstituted C₁₋₈ alkyl(for example, methyl), substituted or unsubstituted heterocyclyl (forexample, a substituted or unsubstituted triazolyl or pyrazolyl),aminocarbonyl, halogen (for example, fluorine), cyano, hydroxyalkyl andhydroxy. In other embodiments, R¹ is pyridyl substituted with one ormore substituents independently selected from the group consisting ofsubstituted or unsubstituted C₁₋₈ alkyl (for example, methyl),substituted or unsubstituted heterocyclyl (for example, a substituted orunsubstituted triazolyl), halogen, aminocarbonyl, cyano, hydroxyalkyl(for example, hydroxypropyl), —OR, and —NR₂, wherein each R isindependently H, or a substituted or unsubstituted C₁₋₄ alkyl. In someembodiments, R¹ is 1H-pyrrolo[2,3-b]pyridyl or benzimidazolyl,optionally substituted with one or more substituents independentlyselected from the group consisting of substituted or unsubstituted C₁₋₈alkyl, and —NR₂, wherein R is independently H, or a substituted orunsubstituted C₁₋₄ alkyl.

In some embodiments, R¹ is

wherein R is at each occurrence independently H, or a substituted orunsubstituted C₁₋₄ alkyl (for example, methyl); R′ is at each occurrenceindependently a substituted or unsubstituted C₁₋₄ alkyl (for example,methyl), halogen (for example, fluoro), cyano, —OR, or —NR₂; m is 0-3;and n is 0-3. It will be understood by those skilled in the art that anyof the substitutents R′ may be attached to any suitable atom of any ofthe rings in the fused ring systems.

In some embodiments of compounds of formula (I), R¹ is

wherein R is at each occurrence independently H, or a substituted orunsubstituted C₁₋₄ alkyl; R′ is at each occurrence independently asubstituted or unsubstituted C₁₋₄ alkyl, halogen, cyano, —OR or —NR₂; mis 0-3; and n is 0-3.

In some embodiments of compounds of formula (I), R² is H, substituted orunsubstituted C₁₋₈ alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedC₁₋₄ alkyl-heterocyclyl, substituted or unsubstituted C₁₋₄ alkyl-aryl,or substituted or unsubstituted C₁₋₄ alkyl-cycloalkyl. For example, R²is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl,tert-butyl, n-pentyl, isopentyl, cyclopentyl, cyclohexyl,tetrahydrofuranyl, tetrahydropyranyl, (C₁₋₄ alkyl)-phenyl, (C₁₋₄alkyl)-cyclopropyl, (C₁₋₄ alkyl)-cyclobutyl, (C₁₋₄ alkyl)-cyclopentyl,(C₁₋₄ alkyl)-cyclohexyl, (C₁₋₄ alkyl)-pyrrolidyl, (C₁₋₄alkyl)-piperidyl, (C₁₋₄ alkyl)-piperazinyl, (C₁₋₄ alkyl)-morpholinyl,(C₁₋₄ alkyl)-tetrahydrofuranyl, or (C₁₋₄ alkyl)-tetrahydropyranyl, eachoptionally substituted.

In other embodiments, R² is H, C₁₋₄ alkyl, (C₁₋₄alkyl)(OR),

wherein R is at each occurrence independently H, or a substituted orunsubstituted C₁₋₄ alkyl (for example, methyl); R′ is at each occurrenceindependently H, —OR, cyano, or a substituted or unsubstituted C₁₋₄alkyl (for example, methyl); and p is 0-3.

In other embodiments of compounds of formula (I), R² is H, C₁₋₄ alkyl,(C₁₋₄alkyl)(OR),

wherein R is at each occurrence independently H, or a substituted orunsubstituted C₁₋₂ alkyl; R′ is at each occurrence independently H, —OR,cyano, or a substituted or unsubstituted C₁₋₂ alkyl; and p is 0-1.

In other embodiments of compounds of formula (I), R³ is H.

In some such embodiments described herein, R¹ is substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl. Forexample, R¹ is phenyl, pyridyl, pyrimidyl, benzimidazolyl,1H-pyrrolo[2,3-b]pyridyl, indazolyl, indolyl, 1H-imidazo[4,5-b]pyridine,pyridyl, 1H-imidazo[4,5-b]pyridin-2(3H)-onyl, 3H-imidazo[4,5-b]pyridyl,or pyrazolyl, each optionally substituted. In some embodiments, R¹ isphenyl substituted with one or more substituents independently selectedfrom the group consisting of substituted or unsubstituted C₁₋₈ alkyl,substituted or unsubstituted heterocyclyl, aminocarbonyl, halogen,cyano, hydroxyalkyl and hydroxy. In others, R¹ is pyridyl substitutedwith one or more substituents independently selected from the groupconsisting of C₁₋₈ alkyl, substituted or unsubstituted heterocyclyl,halogen, aminocarbonyl, cyano, hydroxyalkyl, —OR, and —NR₂, wherein eachR is independently H, or a substituted or unsubstituted C₁₋₄ alkyl. Instill others, R¹ is 1H-pyrrolo[2,3-b]pyridyl or benzimidazolyl,optionally substituted with one or more substituents independentlyselected from the group consisting of substituted or unsubstituted C₁₋₈alkyl, and —NR₂, wherein R is independently H, or a substituted orunsubstituted C₁₋₄ alkyl.

In certain embodiments, the compounds of formula (I) have an R¹ groupset forth herein and an R² group set forth herein.

In some embodiments of compounds of formula (I), the compound inhibitsTOR kinase. In other embodiments of compounds of formula (I), thecompound inhibits DNA-PK. In certain embodiments of compounds of formula(I), the compound inhibits both TOR kinase and DNA-PK.

In some embodiments of compounds of formula (I), the compound at aconcentration of 10 μM inhibits TOR kinase, DNA-PK, PI3K, or acombination thereof by at least about 50%. Compounds of formula (I) maybe shown to be inhibitors of the kinases above in any suitable assaysystem.

Representative TOR kinase inhibitors of formula (I) include compoundsfrom Table A.

TABLE A7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-((trans-4-methoxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(cis-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-((cis-4-methoxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-ethyl-7-(1H-pyrrolo[3,2-b]pyridin-5-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-((cis-4-methoxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(1H-benzo[d]imidazol-4-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-((trans-4-methoxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-((trans-4-hydroxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(cis-4-hydroxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(cis-4-hydroxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-ethyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-((cis-4-hydroxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(tetrahydro-2H-pyran-4-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(1H-indol-4-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-((trans-4-hydroxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-((cis-4-hydroxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(trans-4-hydroxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-isopropyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(trans-4-hydroxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-isopropyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-ethyl-7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(2-hydroxypyridin-4-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-isopropyl-7-(4-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;5-(8-isopropyl-7-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)-4-methylpicolinamide;7-(1H-indazol-4-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(2-aminopyrimidin-5-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(2-aminopyridin-4-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(methylamino)pyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-hydroxypyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(4-(1H-pyrazol-3-yl)phenyl)-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(pyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(1H-indazol-4-yl)-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(1H-indazol-6-yl)-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(pyrimidin-5-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-methoxypyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-(2-methoxyethyl)-7-(1H-pyrrolo[2,3-b]pyridin-5-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-ethyl-7-(1H-pyrrolo[2,3-b]pyridin-5-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-ethyl-7-(1H-indazol-4-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(pyridin-4-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-aminopyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-methyl-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;2-(2-hydroxypropan-2-yl)-5-(8-(trans-4-methoxycyclohexyl)-7-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)pyridine 1-oxide;4-methyl-5-(7-oxo-8-((tetrahydro-2H-pyran-4-yl)methyl)-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)picolinamide;5-(8-((cis-4-methoxycyclohexyl)methyl)-7-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)-4-methylpicolinamide;7-(1H-pyrazol-4-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-(trans-4-methoxycyclohexyl)-7-(4-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;3-((7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-2-oxo-3,4-dihydropyrazino[2,3-b]pyrazin-1(2H)-yl)methyl)benzonitrile;1-((trans-4-methoxycyclohexyl)methyl)-7-(4-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;3-(7-oxo-8-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)benzamide;5-(8-((trans-4-methoxycyclohexyl)methyl)-7-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)-4-methylpicolinamide;3-((7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-2-oxo-3,4-dihydropyrazino[2,3-b]pyrazin-1(2H)-yl)methyl)benzonitrile;7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((1R,3R)-3-methoxycyclopentyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((1S,3R)-3-methoxycyclopentyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((1S,3S)-3-methoxycyclopentyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((1R,3S)-3-methoxycyclopentyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(1H-indazol-6-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(2-morpholinoethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-(trans-4-hydroxycyclohexyl)-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-(cis-4-hydroxycyclohexyl)-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(2-morpholinoethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-isopropyl-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(1H-imidazo[4,5-b]pyridin-6-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-((cis-4-methoxycyclohexyl)methyl)-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-(trans-4-hydroxycyclohexyl)-7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-(cis-4-hydroxycyclohexyl)-7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;4-(7-oxo-8-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)benzamide;7-(1H-indazol-5-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-((1S,3R)-3-methoxycyclopentyl)-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-((1R,3R)-3-methoxycyclopentyl)-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-((1R,3S)-3-methoxycyclopentyl)-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-((1S,3S)-3-methoxycyclopentyl)-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(1H-indol-5-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-ethyl-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(1H-indol-6-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(4-(2-hydroxypropan-2-yl)phenyl)-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-((trans-4-methoxycyclohexyl)methyl)-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((cis-4-methoxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-(2-methoxyethyl)-7-(4-methyl-2-(methylamino)-1H-benzo[d]imidazol-6-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(7-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-(2-methoxyethyl)-7-(4-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-benzyl-7-(2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(3-fluoro-4-(4H-1,2,4-triazol-3-yl)phenyl)-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(3-fluoro-4-(4H-1,2,4-triazol-3-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(3-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-(trans-4-methoxycyclohexyl)-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(5-fluoro-2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(3-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-(2-methoxyethyl)-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((trans-4-methoxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-(cyclopentylmethyl)-7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(4-(2-hydroxypropan-2-yl)phenyl)-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;(S)-7-(6-(1-hydroxyethyl)pyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;(R)-7-(6-(1-hydroxyethyl)pyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(4-(2-hydroxypropan-2-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(4-(trifluoromethyl)benzyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(3-(trifluoromethyl)benzyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(3-methoxypropyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(4-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(4-methyl-2-(methylamino)-1H-benzo[d]imidazol-6-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(2-amino-4-methyl-1H-benzo[d]imidazol-6-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;(R)-7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3-methyl-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;(S)-7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3-methyl-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,3-dimethyl-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(2-amino-4-methyl-1H-benzo[d]imidazol-6-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(4-(1H-1,2,4-triazol-5-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-(1-hydroxypropan-2-yl)-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; and1-(2-hydroxyethyl)-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one, and pharmaceutically acceptable salts, clathrates,solvates, stereoisomers, tautomers, metabolites, isotopologues andprodrugs thereof.

5.3 Methods for Making TOR Kinase Inhibitors

The TOR kinase inhibitors can be obtained via standard, well-knownsynthetic methodology, see e.g., March, J. Advanced Organic Chemistry;Reactions Mechanisms, and Structure, 4th ed., 1992. Starting materialsuseful for preparing compounds of formula (III) and intermediatestherefore, are commercially available or can be prepared fromcommercially available materials using known synthetic methods andreagents.

Particular methods for preparing compounds of formula (I) are disclosedin U.S. Pat. No. 8,110,578, issued Feb. 7, 2012, and U.S. Pat. No.8,569,494, issued Oct. 29, 2013, each incorporated by reference hereinin their entirety.

5.4 Compound AA

N-(3-(5-fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4-ylamino)phenyl)acrylamide:

and pharmaceutically acceptable salts thereof are referred to hereincollectively as “Compound AA.” In one embodiment, the besylate salt ofCompound AA is used in the compositions and methods provided herein. Inone embodiment, the free base of Compound AA is used in the compositionsand methods provided herein.

United States published patent application number US 2010/0029610,published Feb. 4, 2010 (“the '610 publication,” the entirety of which ishereby incorporated herein by reference), describes Compound AA, whichis designated as compound number I-182 in the '610 publication. CompoundAA covalently and irreversibly inhibits activity of one or more proteinkinases, including BTK, a member of TEC-kinases. The synthesis ofCompound AA is described in detail at Example 20 of the '610publication. Compound AA is active in a variety of assays andtherapeutic models demonstrating covalent, irreversible inhibition ofBTK (in enzymatic and cellular assays). Notably, Compound AA is apotent, selective, orally available, small molecule which was found toinhibit B-cell proliferation and activation.

5.5 Anti-CD20 Antibodies

CD20, the first B-cell specific antigen defined by the monoclonalantibody tositumomab, plays a critical role in B-cell development. HumanCD20 is a 297 amino acid (30- to 35-kDa) phosphoprotein with fourtransmembrane domains encoded by the gene MS4A1 located on chromosome11q12.2. CD20 plays a critical role in B-cell development and is abiomarker for immunotherapies targeting B-cell derived diseases. CD20 isan integral membrane protein expressed by B lymphocytes in early stagesof differentiation and by most B cell lymphomas, but not bydifferentiated plasma cells. CD20 remains on the membrane of B cellswithout dissociation or internalization upon antibody binding. CD20functions though binding to the Src family of tyrosine kinases, such asLyn, Fyn and Lck, and believed to be involved as a result in thephosphorylation cascade of intracellular proteins. Anti-CD20 antibodiesare broadly classified into type I and type II antibodies. Both types ofanti-CD 20 antibodies exhibit equal ability in activating Fc-FcγRinteractions such as antibody-dependent cellular cytotoxicity (ADCC) andphagocytosis. Type I anti-CD20 antibodies redistribute CD20 intomembrane lipid rafts and potently activate complement-dependentcytotoxicity (CDC). Type II anti-CD20 antibodies weakly activate CDC butmore potently induce direct programmed cell death.

A person of ordinary skill in the art can readily identify and selectadditional anti-CD20 antibodies that are useful in the presentinvention. For example, in some embodiments, such antibodies aredescribed, for example, in U.S. Pat. Nos. 8,153,125, 8,147,832,8,101,179, 8,084,582, 8,057,793 and 7,879,984, and U.S. PatentPublication Nos. 2011/0129412, 2012/0183545, 2012/0134990 and2012/0034185.

In some embodiments, an anti-CD20 antibody for use in the presentinvention is a type I antibody. In some embodiments, an anti-CD20 foruse in the present invention is a type II antibody.

In some embodiments, an anti-CD20 antibody is an antibody that binds toa CD20 epitope selected from 170ANPS173 and 182YCYSI185.

In some embodiments, an anti-CD20 antibody has a binding affinity (Kd)for an epitope of CD20 of less than 12 nM, less than 11 nM, less than 10nM, less than 9 nM, less than 8 nM, less than 7 nM, less than 6 nM, lessthan 5 nM, less than 4 nM, less than 3 nM, less than 2 nM or less than 1nM.

Rituximab is but one example of an anti-CD20 antibody. In someembodiments, an anti-CD20 antibody for use in the present inventionincludes, for example, rituximab (Rituxan® or MabThera®), Gazyva® (i.e.,obinutuzumab) and Arzerra® (ofatumumab). For ease of reference, providedmethods and regimens detailed herein refer to an exemplary anti-CD20antibody (i.e., rituximab); however, such reference is not intended tolimit the present invention to a single anti-CD20 antibody. Indeed, allreferences to rituximab, or a biosimilar thereof, are to be read by aperson skilled in the art to encompass the class of anti-CD20antibodies. For example, it will be appreciated that the anti-CD20antibodies ofatumumab (Arzerra®) or obinutuzumab (Gazyva®) can insteadbe administered in each instance where reference is made to a CD20antibody or rituximab. In some such embodiments, ofatumumab isadministered in 12 doses according to the following schedule: 300 mginitial dose, followed 1 week later by 2000 mg dose weekly for 7 doses,followed 4 weeks later by 2000 mg every 4 weeks for 4 doses. In somesuch embodiments, obinutuzumab is administered for six 28-day cycles asfollows: 100 mg on day 1, cycle 1; 900 mg on day 2 cycle 1; 1000 mg ondays 8 and 15 of cycle 1; and 1000 mg on day 1 of cycles 2-6.Accordingly, in some embodiments, the term “rituximab” encompasses allcorresponding anti-CD20 antibodies that fulfill the requirementsnecessary for obtaining a marketing authorization as an identical orbiosimilar product in a country or territory selected from the group ofcountries consisting of the USA, Europe and Japan.

In some embodiments, an anti-CD20 antibody has the same or similaractivity as rituximab, or a biosimilar thereof. In some embodiments, ananti-CD20 antibody binds to the same or similar region or epitope asrituximab or a fragment thereof. In some embodiments, an anti-CD20antibody competes with the binding of rituximab or a fragment thereof toCD20. In some embodiments, an anti-CD20 antibody is bioequivalent torituximab or a fragment thereof. In some embodiments, an anti-CD20antibody is a biosimilar of rituximab or a fragment thereof. In someembodiments, an anti-CD20 antibody is a variant or derivative ofrituximab, including functional fragments, derivatives, or antibodyconjugates.

Rituximab (Rituxan® or MabThera®) is a genetically engineered cytolytic,chimeric murine/human monoclonal IgG1 kappa antibody directed againstthe CD20 cell-surface molecule present in normal B lymphocytes andB-cell CLL and in most forms of non-Hodgkin's B-cell lymphomas.Rituximab has a binding affinity for the CD20 antigen of approximately8.0 nM. Rituximab can induce complement-dependent cellular cytotoxicity(CDC) and antibody-dependent cellular cytotoxicity (ADCC), leading toits clinical activity against lymphoma cells. Rituximab can also lead toapoptosis of B cells upon binding to CD20, thereby leading to directinhibition of cellular growth.

Rituximab is produced by mammalian cell (Chinese Hamster Ovary)suspension culture in a nutrient medium containing the antibioticgentamicin. Gentamicin is not detectable in the final product. Rituximabis a sterile, clear, colorless, preservative-free liquid concentrate forintravenous administration. Rituximab is supplied at a concentration of10 mg/mL in either 100 mg/10 mL or 500 mg/50 mL single-use vials.Rituximab is formulated in polysorbate 80 (0.7 mg/mL), sodium citratedihydrate (7.35 mg/mL), sodium chloride (9 mg/mL) and water forinjection. The pH of Rituxan® (or MabThera®) is 6.5

Rituximab has been investigated in clinical studies and approved fortreatment of patients with CLL in combination with fludarabine andcyclophosphamide, as well as patients with rheumatoid arthritis incombination with methotrexate. Rituximab is also approved for treatmentof non-Hodgkin's lymphoma, Wegener's Granulomatosis and MicroscopicPolyangiitis.

5.6 Methods of Use

Provided herein are methods for treating or preventing a cancer,comprising administering an effective amount of a TOR kinase inhibitorand an effective amount of Compound AA to a patient having a cancer.

In certain embodiments, the cancer is a bloodborne tumor.

In certain embodiments, the cancer is a lymphoma, a leukemia or amultiple myeloma.

In certain embodiments, the cancer is non-Hodgkin's lymphoma. In certainembodiments, the non-Hodgkin's lymphoma is diffuse large B-cell lymphoma(DLBCL), follicular lymphoma (FL), acute myeloid leukemia (AML), mantlecell lymphoma (MCL), or ALK⁺ anaplastic large cell lymphoma. In oneembodiment, the non-Hodgkin's lymphoma is advanced solid non-Hodgkin'slymphoma. In one embodiment, the non-Hodgkin's lymphoma is diffuse largeB-cell lymphoma (DLBCL).

In certain embodiments, the cancer is diffuse large B-cell lymphoma(DLBCL).

In certain embodiments, the cancer is a B-cell lymphoma.

In certain embodiments, the B-cell lymphoma is a B-cell non-Hodgkin'slymphoma selected from diffuse large B-cell lymphoma, Burkitt'slymphoma/leukemia, mantle cell lymphoma, mediastinal (thymic) largeB-cell lymphoma, follicular lymphoma, marginal zone lymphoma (includingextranodal marginal zone B-cell lymphoma and nodal marginal zone B-celllymphoma), lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia. Insome embodiments, the B-cell lymphoma is chronic lymphocyticleukemia/small lymphocytic lymphoma (CLL/SLL). In one embodiment, theB-cell lymphoma is Waldenstrom macroglobulinemia. In other embodiments,the CLL is characterized as the small lymphocytic lymphoma (SLL) variantof CLL.

In one embodiment, the B-cell non-Hodgkin's lymphoma is refractoryB-cell non-Hodgkin's lymphoma. In one embodiment, the B-cellnon-Hodgkin's lymphoma is relapsed B-cell non-Hodgkin's lymphoma.

In certain embodiments, the cancer is a T-cell lymphoma.

The B-cell disorders chronic lymphocytic leukemia/small lymphocyticlymphoma (CLL/SLL) represent 2 ends of a spectrum of the same diseaseprocess differing in the degree of blood/marrow involvement (CLL) versuslymph node involvement (SLL).

In other embodiments, the cancer is a multiple myeloma.

In certain embodiments, the cancer is a cancer of the head, neck, eye,mouth, throat, esophagus, bronchus, larynx, pharynx, chest, bone, lung,colon, rectum, stomach, prostate, urinary bladder, uterine, cervix,breast, ovaries, testicles or other reproductive organs, skin, thyroid,blood, lymph nodes, kidney, liver, pancreas, and brain or centralnervous system.

In other embodiments, the cancer is a solid tumor. In certainembodiments, the solid tumor is a relapsed or refractory solid tumor.

In one embodiment, the solid tumor is a neuroendocrine tumor. In certainembodiments, the neuroendocrine tumor is a neuroendocrine tumor of gutorigin. In certain embodiments, the neuroendocrine tumor is ofnon-pancreatic origin. In certain embodiments, the neuroendocrine tumoris non-pancreatic of gut origin. In certain embodiments, theneuroendocrine tumor is of unknown primary origin. In certainembodiments, the neuroendocrine tumor is a symptomatic endocrineproducing tumor or a nonfunctional tumor. In certain embodiments, theneuroendocrine tumor is locally unresectable, metastatic moderate, welldifferentiated, low (grade 1) or intermediate (grade 2).

In one embodiment, the solid tumor is non-small cell lung cancer(NSCLC).

In another embodiment, the solid tumor is glioblastoma multiforme (GBM).

In another embodiment, the solid tumor is hepatocellular carcinoma(HCC).

In another embodiment, the solid tumor is breast cancer. In oneembodiment, the breast cancer is hormone receptor positive. In oneembodiment, the breast cancer is estrogen receptor positive (ER+,ER+/Her2 or ER+/Her2+). In one embodiment, the breast cancer is estrogenreceptor negative (ER−/Her2+). In one embodiment, the breast cancer istriple negative (TN) (breast cancer that does not express the genesand/or protein corresponding to the estrogen receptor (ER), progesteronereceptor (PR), and that does not overexpress the Her2/neu protein).

In another embodiment, the solid tumor is colorectal cancer (CRC).

In another embodiment, the solid tumor is salivary cancer.

In another embodiment, the solid tumor is pancreatic cancer.

In another embodiment, the solid tumor is adenocystic cancer.

In another embodiment, the solid tumor is adrenal cancer.

In another embodiment, the solid tumor is esophageal cancer, renalcancer, leiomyosarcoma, or paraganglioma.

In one embodiment, the solid tumor is an advanced solid tumor.

In another embodiment, the cancer is head and neck squamous cellcarcinoma.

In another embodiment, the cancer is E-twenty six (ETS) overexpressingcastration-resistant prostate cancer.

In another embodiment, the cancer is E-twenty six (ETS) overexpressingEwings sarcoma.

In other embodiments, the cancer is a cancer associated with thepathways involving mTOR, PI3K, or Akt kinases and mutants or isoformsthereof. Other cancers within the scope of the methods provided hereininclude those associated with the pathways of the following kinases:PI3Kα, PI3Kβ, PI3Kδ, KDR, GSK3α, GSK3β, ATM, ATX, ATR, cFMS, and/orDNA-PK kinases and mutants or isoforms thereof. In some embodiments, thecancers associated with mTOR/PI3K/Akt pathways include solid andblood-borne tumors, for example, multiple myeloma, mantle cell lymphoma,diffused large B-cell lymphoma, acute myeloid lymphoma, follicularlymphoma, chronic lymphocytic leukemia; and solid tumors, for example,breast, lung, endometrial, ovarian, gastric, cervical, and prostatecancer; glioblastoma; renal carcinoma; hepatocellular carcinoma; coloncarcinoma; neuroendocrine tumors; head and neck tumors; and sarcomas,such as Ewing's sarcoma.

Further provided herein are methods for treating or preventing a cancer,comprising administering an effective amount of Compound AA (e.g., aloneor in the absence of a TOR kinase inhibitor) to a patient having acancer.

In certain embodiments wherein Compound AA is administered alone or inthe absence of a TOR kinase inhibitor, the cancer is a cancer of thehead, neck, eye, mouth, throat, esophagus, bronchus, larynx, pharynx,chest, bone, lung, colon, rectum, stomach, prostate, urinary bladder,uterine, cervix, breast, ovaries, testicles or other reproductiveorgans, skin, thyroid, blood, lymph nodes, kidney, liver, pancreas, andbrain or central nervous system.

In other embodiments wherein Compound AA is administered alone or in theabsence of a TOR kinase inhibitor, the cancer is a solid tumor. Incertain embodiments, the solid tumor is a relapsed or refractory solidtumor.

In one embodiment wherein Compound AA is administered alone or in theabsence of a TOR kinase inhibitor, the solid tumor is a neuroendocrinetumor. In certain embodiments, the neuroendocrine tumor is aneuroendocrine tumor of gut origin. In certain embodiments, theneuroendocrine tumor is of non-pancreatic origin. In certainembodiments, the neuroendocrine tumor is non-pancreatic of gut origin.In certain embodiments, the neuroendocrine tumor is of unknown primaryorigin. In certain embodiments, the neuroendocrine tumor is asymptomatic endocrine producing tumor or a nonfunctional tumor. Incertain embodiments, the neuroendocrine tumor is locally unresectable,metastatic moderate, well differentiated, low (grade 1) or intermediate(grade 2).

In one embodiment wherein Compound AA is administered alone or in theabsence of a TOR kinase inhibitor, the solid tumor is non-small celllung cancer (NSCLC).

In another embodiment wherein Compound AA is administered alone or inthe absence of a TOR kinase inhibitor, the solid tumor is glioblastomamultiforme (GBM).

In another embodiment wherein Compound AA is administered alone or inthe absence of a TOR kinase inhibitor, the solid tumor is hepatocellularcarcinoma (HCC).

In another embodiment wherein Compound AA is administered alone or inthe absence of a TOR kinase inhibitor, the solid tumor is breast cancer.In one embodiment, the breast cancer is hormone receptor positive. Inone embodiment, the breast cancer is estrogen receptor positive (ER+,ER+/Her2 or ER+/Her2+). In one embodiment, the breast cancer is estrogenreceptor negative (ER−/Her2+). In one embodiment, the breast cancer istriple negative (TN) (breast cancer that does not express the genesand/or protein corresponding to the estrogen receptor (ER), progesteronereceptor (PR), and that does not overexpress the Her2/neu protein).

In another embodiment wherein Compound AA is administered alone or inthe absence of a TOR kinase inhibitor, the solid tumor is colorectalcancer (CRC).

In another embodiment wherein Compound AA is administered alone or inthe absence of a TOR kinase inhibitor, the solid tumor is salivarycancer.

In another embodiment wherein Compound AA is administered alone or inthe absence of a TOR kinase inhibitor, the solid tumor is pancreaticcancer.

In another embodiment wherein Compound AA is administered alone or inthe absence of a TOR kinase inhibitor, the solid tumor is adenocysticcancer.

In another embodiment wherein Compound AA is administered alone or inthe absence of a TOR kinase inhibitor, the solid tumor is adrenalcancer.

In another embodiment wherein Compound AA is administered alone or inthe absence of a TOR kinase inhibitor, the solid tumor is esophagealcancer, renal cancer, leiomyosarcoma, or paraganglioma.

In one embodiment wherein Compound AA is administered alone or in theabsence of a TOR kinase inhibitor, the solid tumor is an advanced solidtumor.

In another embodiment wherein Compound AA is administered alone or inthe absence of a TOR kinase inhibitor, the cancer is head and necksquamous cell carcinoma.

In another embodiment wherein Compound AA is administered alone or inthe absence of a TOR kinase inhibitor, the cancer is E-twenty six (ETS)overexpressing castration-resistant prostate cancer.

In another embodiment wherein Compound AA is administered alone or inthe absence of a TOR kinase inhibitor, the cancer is E-twenty six (ETS)overexpressing Ewings sarcoma.

In other embodiments wherein Compound AA is administered alone or in theabsence of a TOR kinase inhibitor, the cancer is a cancer associatedwith the pathways involving mTOR, PI3K, or Akt kinases and mutants orisoforms thereof. Other cancers within the scope of the methods providedherein include those associated with the pathways of the followingkinases: PI3Kα, PI3Kβ, PI3Kδ, KDR, GSK3α, GSK3β, ATM, ATX, ATR, cFMS,and/or DNA-PK kinases and mutants or isoforms thereof. In someembodiments, the cancers associated with mTOR/PI3K/Akt pathways includesolid and blood-borne tumors, for example, multiple myeloma, mantle celllymphoma, diffused large B-cell lymphoma, acute myeloid lymphoma,follicular lymphoma, chronic lymphocytic leukemia; and solid tumors, forexample, breast, lung, endometrial, ovarian, gastric, cervical, andprostate cancer; glioblastoma; renal carcinoma; hepatocellularcarcinoma; colon carcinoma; neuroendocrine tumors; head and neck tumors;and sarcomas, such as Ewing's sarcoma.

In certain embodiments wherein Compound AA is administered alone or inthe absence of a TOR kinase inhibitor, the cancer is acute myeloidleukemia.

In certain embodiments wherein Compound AA is administered alone or inthe absence of a TOR kinase inhibitor, the cancer is ALK⁺ anaplasticlarge cell lymphoma.

In certain embodiments wherein Compound AA is administered alone or inthe absence of a TOR kinase inhibitor, the cancer is a T-cell lymphoma.

In certain embodiments, provided herein are methods for achieving anInternational Workshop on Chronic Lymphocytic Leukemia (IWCLL) responsedefinition of a complete response, partial response or stable disease ina patient having chronic lymphocytic leukemia, comprising administeringan effective amount of a TOR kinase inhibitor in combination withCompound AA to said patient. In certain embodiments, provided herein aremethods for achieving a Response Evaluation Criteria in Solid Tumors(for example, RECIST 1.1) of complete response, partial response orstable disease in a patient having a solid tumor, comprisingadministering an effective amount of a TOR kinase inhibitor incombination with Compound AA to said patient. In certain embodiments,provided herein are methods for achieving a National CancerInstitute-Sponsored Working Group on Chronic Lymphocytic Leukemia(NCI-WG CLL) response definition of complete response, partial responseor stable disease in a patient having leukemia, comprising administeringan effective amount of a TOR kinase inhibitor in combination withCompound AA to said patient. In certain embodiments, provided herein aremethods for achieving a Prostate Cancer Working Group 2 (PCWG2) Criteriaof complete response, partial response or stable disease in a patienthaving prostate cancer, comprising administering an effective amount ofa TOR kinase inhibitor in combination with Compound AA to said patient.In certain embodiments, provided herein are methods for achieving anInternational Workshop Criteria (IWC) for non-Hodgkin's lymphoma ofcomplete response, partial response or stable disease in a patienthaving non-Hodgkin's lymphoma, comprising administering an effectiveamount of a TOR kinase inhibitor in combination with Compound AA to saidpatient. In certain embodiments, provided herein are methods forachieving an International Uniform Response Criteria (IURC) for multiplemyeloma of complete response, partial response or stable disease in apatient having multiple myeloma, comprising administering an effectiveamount of a TOR kinase inhibitor in combination with Compound AA to saidpatient. In certain embodiments, provided herein are methods forachieving a Responses Assessment for Neuro-Oncology (RANO) Working Groupfor glioblastoma multiforme of complete response, partial response orstable disease in a patient having glioblastoma multiforme, comprisingadministering an effective amount of a TOR kinase inhibitor incombination with Compound AA to said patient.

In certain embodiments, provided herein are methods for increasingsurvival without disease progression of a patient having a cancer,comprising administering an effective amount of a TOR kinase inhibitorin combination with an effective amount of Compound AA to said patient.

In certain embodiments, provided herein are methods for treating acancer, the methods comprising administering an effective amount of aTOR kinase inhibitor in combination with an effective amount of CompoundAA to a patient having a cancer, wherein the treatment results inprevention or retarding of clinical progression, such as cancer-relatedcachexia or increased pain.

In some embodiments, provided herein are methods for treating a cancer,the methods comprising administering an effective amount of a TOR kinaseinhibitor in combination with an effective amount of Compound AA to apatient having a B-cell lymphoma, wherein the treatment results in oneor more of inhibition of disease progression, increased Time ToProgression (TTP), increased Progression Free Survival (PFS), and/orincreased Overall Survival (OS), among others.

In some embodiments, the TOR kinase inhibitor is a compound as describedherein. In one embodiment, the TOR kinase inhibitor is a compound offormula (I). In one embodiment, the TOR kinase inhibitor is a compoundfrom Table A. In one embodiment, the TOR kinase inhibitor is Compound 1(a TOR kinase inhibitor set forth herein having molecular formulaC₂₁H₂₇N₅O₃). In one embodiment, the TOR kinase inhibitor is Compound 2(a TOR kinase inhibitor set forth herein having molecular formulaC₁₆H₁₆N₈O). In one embodiment, the TOR kinase inhibitor is Compound 3 (aTOR kinase inhibitor set forth herein having molecular formulaC₂₀H₂₅N₅O₃). In one embodiment, Compound 1 is7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((1r,4r)-4-methoxycyclohexyl)-3,4-dihydropyrazino-[2,3-b]pyrazin-2(1H)-one,alternatively named7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((trans)-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one,or7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((1R*,4R*)-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one.In another embodiment, Compound 2 is1-ethyl-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one,or a tautomer thereof, for example,1-ethyl-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one,or1-ethyl-7-(2-methyl-6-(1H-1,2,4-triazol-5-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one.In another embodiment, Compound 3 is1-((trans)-4-hydroxycyclohexyl)-7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one,alternatively named1-((1r,4r)-4-hydroxycyclohexyl)-7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one.In one embodiment, Compound 3 is a metabolite of Compound 1.

A TOR kinase inhibitor administered in combination with Compound AA canbe further combined with radiation therapy or surgery. In certainembodiments, a TOR kinase inhibitor is administered in combination withCompound AA to patient who is undergoing radiation therapy, haspreviously undergone radiation therapy or will be undergoing radiationtherapy. In certain embodiments, a TOR kinase inhibitor is administeredin combination with Compound AA to a patient who has undergone surgery,such as tumor removal surgery.

Further provided herein are methods for treating patients who have beenpreviously treated for a cancer, as well as those who have notpreviously been treated. Because patients with a cancer haveheterogenous clinical manifestations and varying clinical outcomes, thetreatment given to a patient may vary, depending on his/her prognosis.The skilled clinician will be able to readily determine without undueexperimentation specific secondary agents, types of surgery, and typesof non-drug based standard therapy that can be effectively used to treatan individual patient with a cancer.

In one embodiment, a TOR kinase inhibitor is administered in combinationwith Compound AA and an anti-CD20 antibody, for example, rituximab(Rituxan® or MabThera®). Accordingly, provided herein are methods fortreating or preventing a cancer, comprising administering an effectiveamount of a TOR kinase inhibitor, an effective amount of Compound AA andan effective amount of an anti-CD20 antibody, for example, rituximab(Rituxan® or MabThera®) to a patient having a cancer. In a specificembodiment, Compound 1 is administered in combination with Compound AAand an anti-CD20 antibody, for example, rituximab (Rituxan® orMabThera®). In a particular embodiment, the cancer treated or preventedwith a combination of a TOR kinase inhibitor, Compound AA and ananti-CD20 antibody, for example, rituximab (Rituxan® or MabThera®) isdiffuse large B-cell lymphomas (DLBCL).

In certain embodiments, a TOR kinase inhibitor is administered incombination with Compound AA to a patient in cycles. Cycling therapyinvolves the administration of an active agent(s) for a period of time,followed by a rest for a period of time, and repeating this sequentialadministration. Cycling therapy can reduce the development ofresistance, avoid or reduce the side effects, and/or improves theefficacy of the treatment. The administration of a TOR kinase inhibitor,Compound AA and an anti-CD20 antibody, for example, rituximab (Rituxan®or MabThera®), in combination can also be carried out in such cycles.

In some embodiments, Compound AA is administered twice daily, or BID,whereas a TOR kinase inhibitor is administered once daily, or QD.Alternatively and/or additionally, Compound AA may be administered onceor twice daily for one or more 28 day cycles, whereas a TOR kinaseinhibitor may be administered once daily for days 1 through 21 of one ormore 28-day cycles. In some embodiments, Compound AA is administeredtwice daily on days 1 through 28 of one or more 28-day cycles and a TORkinase inhibitor is administered once daily on days 2 through 22 of oneor more 28-day cycles. In some embodiments, Compound AA is administeredtwice daily on days 1 through 28 of one or more 28-day cycles and a TORkinase inhibitor is administered once daily on days 1 through 28 of oneor more 28-day cycles.

In some embodiments, a TOR kinase inhibitor is administered once daily,or QD, Compound AA is administered twice daily, or BID, and an anti-CD20antibody, for example, rituximab (Rituxan® or MabThera®), isadministered once monthly or once every 4 weeks. Alternatively and/oradditionally, in one or more 28-day cycles, a TOR kinase inhibitor maybe administered once daily, Compound AA may be administered once ortwice daily and an anti-CD20 antibody, for example, rituximab (Rituxan®or MabThera®), may be administered once.

In some embodiments, provided methods comprise administering Compound AAin combination with a TOR kinase inhibitor daily for a period of 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,23, 24, 25, 26, 27 or 28 days. In some embodiments, a treatment regimencomprises at least one 28-day cycle. As used herein, the term “28-daycycle” means that the combination of Compound AA and a TOR kinaseinhibitor is administered to a patient in need thereof for 28consecutive days. In some embodiments, the combination of Compound AAand a TOR kinase inhibitor is administered for at least one 28-daycycle. In some embodiments, the combination of Compound AA and a TORkinase inhibitor is administered for at least two, at least three, atleast four, at least five or at least six 28-day cycles. In someembodiments, the combination of Compound AA and a TOR kinase inhibitoris administered for at least seven, at least eight, at least nine, atleast ten, at least eleven or at least twelve 28-day cycles. In someembodiments, the combination of Compound AA and a TOR kinase inhibitoris administered for at least thirteen, at least fourteen, at leastfifteen, at least sixteen, at least seventeen or at least eighteen28-day cycles.

In some embodiments, the combination of Compound AA and a TOR kinaseinhibitor is administered for at least eighteen 28-day cycles, andCompound AA is further administered for at least one additional 28-daycycle. In some embodiments, the combination of Compound AA and a TORkinase inhibitor is administered for at least eighteen 28-day cycles,and Compound AA is further administered for at least two, at leastthree, at least four, at least five, at least six, at least seven, atleast eight, at least nine, at least ten, at least eleven or at leasttwelve additional 28-day cycles. In some embodiments, the combination ofCompound AA and a TOR kinase inhibitor is administered for at leasteighteen 28-day cycles, and Compound AA is further administered for atleast thirteen, at least fourteen, at least fifteen, at least sixteen,at least seventeen, at least eighteen, at least nineteen, at leasttwenty, at least twenty-one, at least twenty-two, at least twenty-threeor at least twenty-four additional 28-day cycles. In some embodiments,the combination of Compound AA and a TOR kinase inhibitor isadministered to a patient for the duration of the patient's life. Insome embodiments, the combination of Compound AA and a TOR kinaseinhibitor is administered for at least eighteen 28-day cycles, andCompound AA is further administered for the duration of the patient'slife. In some embodiments, Compound AA is administered on days 1 through28 (for example, one dose each day or two doses each day) of each 28-daycycle and Compound AA is administered on days 1 through 21 (for example,one dose each day) of one or more 28-day cycles. In some embodiments,Compound AA is administered on days 1 through 28 of one or more 28-daycycles and Compound AA is administered on days 2 through 22 of one ormore 28-day cycles.

In some embodiments, two adjacent 28-day cycles may be separated by arest period. Such a rest period may be one, two, three, four, five, six,seven or more days during which the patient is not administered eitheror both Compound AA and a TOR kinase inhibitor. In a preferredembodiment, two adjacent 28-day cycles are continuous.

In one embodiment, a TOR kinase inhibitor is administered in combinationwith Compound AA daily in single or divided doses for about 3 days,about 5 days, about one week, about two weeks, about three weeks, aboutfour weeks (e.g., 28 days), about five weeks, about six weeks, aboutseven weeks, about eight weeks, about ten weeks, about fifteen weeks, orabout twenty weeks, followed by a rest period of about 1 day to aboutten weeks. In one embodiment, the methods provided herein contemplatecycling treatments of about one week, about two weeks, about threeweeks, about four weeks, about five weeks, about six weeks, about eightweeks, about ten weeks, about fifteen weeks, or about twenty weeks. Insome embodiments, a TOR kinase inhibitor is administered in combinationwith Compound AA in single or divided doses for about 3 days, about 5days, about one week, about two weeks, about three weeks, about fourweeks (e.g., 28 days), about five weeks, or about six weeks with a restperiod of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 22,24, 26, 28, 29, or 30 days. In some embodiments, the rest period is 1day. In some embodiments, the rest period is 3 days. In someembodiments, the rest period is 7 days. In some embodiments, the restperiod is 14 days. In some embodiments, the rest period is 28 days. Thefrequency, number and length of dosing cycles can be increased ordecreased.

In one embodiment, the methods provided herein comprise: i)administering to the subject a first daily dose of a TOR kinaseinhibitor in combination with Compound AA; ii) optionally resting for aperiod of at least one day where Compound AA is not administered to thesubject; iii) administering a second dose of a TOR kinase inhibitor incombination with Compound AA to the subject; and iv) repeating steps ii)to iii) a plurality of times.

In one embodiment, the methods provided herein comprise administering tothe subject a dose of Compound AA on day 1, followed by administering aTOR kinase inhibitor in combination with Compound AA to the subject onday 2 and subsequent days.

In certain embodiments, a TOR kinase inhibitor in combination withCompound AA is administered continuously for between about 1 and about52 weeks. In certain embodiments, a TOR kinase inhibitor in combinationwith Compound AA is administered continuously for about 0.5, 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, or 12 months. In certain embodiments, a TORkinase inhibitor in combination with Compound AA is administeredcontinuously for about 7, about 14, about 21, about 28, about 35, about42, about 84, or about 112 days.

In certain embodiments, when a TOR kinase inhibitor is administered incombination with Compound AA, the TOR kinase inhibitor is administeredcontinuously for 28 days, while Compound AA is administered continuouslyfor 21 days followed by 7 days without administration of Compound AA. Inone embodiment, in a 28 day cycle, Compound AA is administered alone onDay 1, Compound AA and the TOR kinase inhibitor are administered incombination on Days 2-21 and the TOR kinase inhibitor is administeredalone on Days 22-28. In some such embodiments, starting with Cycle 2both Compound AA and the TOR kinase inhibitor are administered on Day 1,Compound AA is continued through Day 21, while the TOR kinase inhibitoris continued through Day 28. The 28 day cycles, as described above, canbe continued for as long needed, such as for 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11 or 12 months or longer.

In certain embodiments, when a TOR kinase inhibitor is administered incombination with Compound AA, in a 28 day cycle, Compound AA isadministered alone on Days 1-7 and the TOR kinase inhibitor isadministered alone on Days 8-28. Such 28 day cycles can be continued foras long needed, such as for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12months or longer.

In certain embodiments, when a TOR kinase inhibitor is administered incombination with Compound AA, the TOR kinase inhibitor is administeredat an amount of about 2.5 mg to about 50 mg per day (such as about 2.5mg, about 10 mg, about 15 mg, about 16 mg/day, about 20 mg, about 30 mgor about 45 mg per day) and Compound AA is administered at an amount ofabout 25 mg to about 1250 mg per day (such as about 25 mg, about 50 mg,about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg,about 200 mg, about 225 mg, about 250 mg, about 375 mg, about 500 mg,about 750 mg, about 1000 mg or about 1250 mg per day). In certainembodiments, about 2.5 mg per day of a TOR kinase inhibitor isadministered in combination with about 25 mg, about 50 mg, about 75 mg,about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg,about 225 mg, about 250 mg, about 375 mg, about 500 mg, about 750 mg,about 1000 mg or about 1250 mg per day of Compound AA. In certainembodiments, about 10 mg per day of a TOR kinase inhibitor isadministered in combination with about 25 mg, about 50 mg, about 75 mg,about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg,about 225 mg, about 250 mg, about 375 mg, about 500 mg, about 750 mg,about 1000 mg or about 1250 mg per day of Compound AA. In certainembodiments, about 15 mg per day of a TOR kinase inhibitor isadministered in combination with about 25 mg, about 50 mg, about 75 mg,about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg,about 225 mg, about 250 mg, about 375 mg, about 500 mg, about 750 mg,about 1000 mg or about 1250 mg per day of Compound AA. In certainembodiments, about 16 mg per day of a TOR kinase inhibitor isadministered in combination with about 25 mg, about 50 mg, about 75 mg,about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg,about 225 mg, about 250 mg, about 375 mg, about 500 mg, about 750 mg,about 1000 mg or about 1250 mg per day of Compound AA. In certainembodiments, about 20 mg per day of a TOR kinase inhibitor isadministered in combination with about 25 mg, about 50 mg, about 75 mg,about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg,about 225 mg, about 250 mg, about 375 mg, about 500 mg, about 750 mg,about 1000 mg or about 1250 mg per day of Compound AA. In certainembodiments, about 30 mg per day of a TOR kinase inhibitor isadministered in combination with about 25 mg, about 50 mg, about 75 mg,about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg,about 225 mg, about 250 mg, about 375 mg, about 500 mg, about 750 mg,about 1000 mg or about 1250 mg per day of Compound AA. In certainembodiments, about 45 mg per day of a TOR kinase inhibitor isadministered in combination with about 25 mg, about 50 mg, about 75 mg,about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg,about 225 mg, about 250 mg, about 375 mg, about 500 mg, about 750 mg,about 1000 mg or about 1250 mg per day of Compound AA. A TOR kinaseinhibitor and Compound AA can each be independently administered once(QD), twice (BD) or three times (TID) per day.

In some embodiments, methods provided herein comprise administering to apatient in need thereof a therapeutically effective amount of a TORkinase inhibitor in combination with Compound AA, wherein thetherapeutically effective amount of Compound AA is about 250 mg to about1250 mg per day. In some embodiments, the therapeutically effectiveamount of Compound AA is administered as one or more discreet doses. Forexample, in some embodiments, a therapeutically effective amount ofCompound AA is 250 mg per day, wherein the therapeutically effectiveamount is administered as 125 mg twice daily (BID). In some embodiments,a therapeutically effective amount of Compound AA is 500 mg per day,wherein the therapeutically effective amount is administered as 250 mgtwice daily (BID). In some embodiments, a therapeutically effectiveamount of Compound AA is 750 mg per day, wherein the therapeuticallyeffective amount is administered as 375 mg twice daily (BID). In someembodiments, a therapeutically effective amount of Compound AA is 1000mg per day, wherein the therapeutically effective amount is administeredas 500 mg twice daily (BID).

In some embodiments, methods provided herein comprise administering to apatient in need thereof a therapeutically effective amount of a TORkinase inhibitor in combination with Compound AA, wherein thetherapeutically effective amount of Compound AA is about 125 mg to about1250 mg per day, or about 125 mg to about 1125 mg per day, or about 125mg to about 1000 mg per day, or about 125 mg to about 875 mg per day, orabout 125 mg to about 750 mg per day, or about 125 mg to about 625 mgper day, or about 125 mg to about 500 mg per day, or about 125 mg toabout 375 mg per day, or about 125 mg to about 250 mg per day, or about250 mg to about 1250 mg per day, or about 250 mg to about 1125 mg perday, or about 250 mg to about 1000 mg per day, or about 250 mg to about875 mg per day, or about 250 mg to about 750 mg per day, or about 250 mgto about 625 mg per day, or about 250 mg to about 500 mg per day, orabout 250 mg to about 375 mg per day, or about 375 mg to about 1250 mgper day, or about 375 mg to about 1125 mg per day, or about 375 mg toabout 1000 mg per day, or about 375 mg to about 875 mg per day, or about375 mg to about 750 mg per day, or about 375 mg to about 625 mg per day,or about 375 mg to about 500 mg per day, or about 500 mg to about 1250mg per day, or about 500 mg to about 1125 mg per day, or about 500 mg toabout 1000 mg per day, or about 500 mg to about 875 mg per day, or about500 mg to about 750 mg per day, or about 500 mg to about 625 mg per day,or about 625 mg to about 1250 mg per day, or about 625 mg to about 1125mg per day, or about 625 mg to about 1000 mg per day, or about 625 mg toabout 875 mg per day, or about 625 mg to about 750 mg per day, or about750 mg to about 1250 mg per day, or about 750 mg to about 1125 mg perday, or about 750 mg to about 1000 mg per day, or about 875 mg to about1250 mg per day, or about 875 mg to about 1125 mg per day, or about 875mg to about 1000 mg per day.

In some embodiments, methods provided herein comprise administering to apatient in need thereof a therapeutically effective amount of a TORkinase inhibitor in combination with Compound AA, wherein thetherapeutically effective amount of Compound AA per day is about 125 mg,130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg,175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg,220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg,265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, 300 mg, 305 mg,310 mg, 315 mg, 320 mg, 325 mg, 330 mg, 335 mg, 340 mg, 345 mg, 350 mg,355 mg, 360 mg, 365 mg, 370 mg, 375 mg, 380 mg, 385 mg, 390 mg, 395 mg,400 mg, 405 mg, 410 mg, 415 mg, 420 mg, 425 mg, 430 mg, 435 mg, 440 mg,445 mg, 450 mg, 455 mg, 460 mg, 465 mg, 470 mg, 475 mg, 480 mg, 485 mg,490 mg, 495 mg, 500 mg, 505 mg, 510 mg, 515 mg, 520 mg, 525 mg, 530 mg,535 mg, 540 mg, 545 mg, 550 mg, 555 mg, 560 mg, 565 mg, 570 mg, 575 mg,580 mg, 585 mg, 590 mg, 595 mg, 600 mg, 605 mg, 610 mg, 615 mg, 620 mg,625 mg, 630 mg, 635 mg, 640 mg, 645 mg, 650 mg, 655 mg, 660 mg, 665 mg,670 mg, 675 mg, 680 mg, 685 mg, 690 mg, 695 mg, 700 mg, 705 mg, 710 mg,715 mg, 720 mg, 725 mg, 730 mg, 735 mg, 740 mg, 745 mg, 750 mg, 755 mg,760 mg, 765 mg, 770 mg, 775 mg, 780 mg, 785 mg, 790 mg, 795 mg, 800 mg,805 mg, 810 mg, 815 mg, 820 mg, 825 mg, 830 mg, 835 mg, 840 mg, 845 mg,850 mg, 855 mg, 860 mg, 865 mg, 870 mg, 875 mg, 880 mg, 885 mg, 890 mg,895 mg, 900 mg, 905 mg, 910 mg, 915 mg, 920 mg, 925 mg, 930 mg, 935 mg,940 mg, 945 mg, 950 mg, 955 mg, 960 mg, 965 mg, 970 mg, 975 mg, 980 mg,985 mg, 990 mg, 995 mg, 1000 mg, 1005 mg, 1010 mg, 1015 mg, 1020 mg,1025 mg, 1030 mg, 1035 mg, 1040 mg, 1045 mg, 1050 mg, 1055 mg, 1060 mg,1065 mg, 1070 mg, 1075 mg, 1080 mg, 1085 mg, 1090 mg, 1095 mg, 1100 mg,1105 mg, 1110 mg, 1115 mg, 1120 mg, 1125 mg, 1130 mg, 1135 mg, 1140 mg,1145 mg, 1150 mg, 1155 mg, 1160 mg, 1165 mg, 1170 mg, 1175 mg, 1180 mg,1185 mg, 1190 mg, 1195 mg, 1200 mg, 1205 mg, 1210 mg, 1215 mg, 1220 mg,1225 mg, 1230 mg, 1235 mg, 1240 mg, 1245 mg or 1250 mg.

In some embodiments, the methods of treatment provided herein compriseadministering to a patient in need thereof about 125 mg BID to about 500mg BID Compound AA in combination with about 2.5 mg to about 50 mg perday (such as about 2.5 mg, about 10 mg, about 15 mg, about 16 mg/day,about 20 mg, about 30 mg or about 45 mg per day) of a TOR kinaseinhibitor. In some embodiments, provided methods comprise administeringto a patient in need thereof 375 mg BID to about 500 mg BID Compound AAin combination with about 2.5 mg to about 50 mg (such as about 2.5 mg,about 10 mg, about 15 mg, about 16 mg/day, about 20 mg, about 30 mg orabout 45 mg per day) of a TOR kinase inhibitor.

In certain embodiments, when a TOR kinase inhibitor is administered incombination with Compound AA, the TOR kinase inhibitor:Compound AA ratiois from about 1:1 to about 1:10. In certain embodiments, when a TORkinase inhibitor is administered in combination with Compound AA, theTOR kinase inhibitor:Compound AA ratio is less than about 1:1, less thanabout 1:3 or less than about 1:10. In certain embodiments, when a TORkinase inhibitor is administered in combination with Compound AA, theTOR kinase inhibitor:Compound AA ratio is about 1:1, about 1:3 or about1:10.

In certain embodiments, the methods provided herein further comprise theadministration of an anti-CD20 antibody, for example, rituximab(Rituxan® or MabThera®), in combination with a TOR kinase inhibitor andCompound AA, wherein the amount of an anti-CD20 antibody, for example,rituximab (Rituxan® or MabThera®), administered is about 250 mg/m² toabout 500 mg/m² once per 28 days, the amount of a TOR kinase inhibitoradministered is about 10 mg to about 40 mg daily and the amount ofCompound AA is about 250 mg to about 750 mg BID. In a particularembodiment, the methods provided herein further comprise theadministration of an anti-CD20 antibody, for example, rituximab(Rituxan® or MabThera®), in combination with a TOR kinase inhibitor andCompound AA, wherein the amount of an anti-CD20 antibody, for example,rituximab (Rituxan® or MabThera®), administered is about 375 mg/m² orabout 500 mg/m² once per 28 days, the amount of a TOR kinase inhibitoradministered is about 20 mg or about 30 mg daily and the amount ofCompound AA administered is about 375 mg or about 500 mg BID.

In some embodiments, provided methods comprise administering to apatient in need thereof a pharmaceutical composition comprisingrituximab, wherein rituximab is administered as an infusion at a rate of50 mg/hr. In some embodiments, the infusion rate of rituximab isincreased by 50 mg/hr every 30 minutes, to a maximum of 400 mg/hr. Insome embodiments, the infusion rate of rituximab is increased by 100mg/hr every 30 minutes, to a maximum of 400 mg/hr. Accordingly, in someembodiments, the infusion rate of rituximab is 100 mg/hr. In someembodiments, the infusion rate of rituximab is 150 mg/hr. In someembodiments, the infusion rate of rituximab is 200 mg/hr. In someembodiments, the infusion rate of rituximab is 250 mg/hr. In someembodiments, the infusion rate of rituximab is 300 mg/hr. In someembodiments, the infusion rate of rituximab is 350 mg/hr. In someembodiments, the infusion rate of rituximab is 400 mg/hr.

In some embodiments, 375 mg/m² rituximab is administered on cycle 1 day2, and 500 mg/m² rituximab is administered on cycle 2 day 1. In someembodiments, 375 mg/m² rituximab is administered on cycle 1 day 2, and500 mg/m² rituximab is administered on each of cycle 2 day 1 and cycle 3day 1. In some embodiments, 375 mg/m² rituximab is administered on cycle1 day 2, and 500 mg/m² rituximab is administered on each of cycle 2 day1, cycle 3 day 1 and cycle 4 day 1. In some embodiments, 375 mg/m²rituximab is administered on cycle 1 day 2, and 500 mg/m² rituximab isadministered on each of cycle 2 day 1, cycle 3 day 1, cycle 4 day 1 andcycle 5 day 1. In some embodiments, 375 mg/m² rituximab is administeredon cycle 1 day 2, and 500 mg/m² rituximab is administered on each ofcycle 2 day 1, cycle 3 day 1, cycle 4 day 1, cycle 5 day 1 and cycle 6day 1.

In certain embodiments, each of the methods provided herein comprisesadministering an effective amount of Compound AA (e.g., alone or in theabsence of a TOR kinase inhibitor) to a patient having a cancer.

5.7 Pharmaceutical Compositions and Routes of Administration

Provided herein are compositions comprising an effective amount of a TORkinase inhibitor and an effective amount of Compound AA and compositionscomprising an effective amount of a TOR kinase inhibitor and Compound AAand a pharmaceutically acceptable carrier or vehicle.

In some embodiments, the pharmaceutical compositions described hereinare suitable for oral, parenteral, mucosal, transdermal or topicaladministration.

The compositions can be administered to a patient orally or parenterallyin the conventional form of preparations, such as capsules,microcapsules, tablets, granules, powder, troches, pills, suppositories,injections, suspensions and syrups. Suitable formulations can beprepared by methods commonly employed using conventional, organic orinorganic additives, such as an excipient (e.g., sucrose, starch,mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphateor calcium carbonate), a binder (e.g., cellulose, methylcellulose,hydroxymethylcellulose, polypropylpyrrolidone, polyvinylpyrrolidone,gelatin, gum arabic, polyethyleneglycol, sucrose or starch), adisintegrator (e.g., starch, carboxymethylcellulose,hydroxypropylstarch, low substituted hydroxypropylcellulose, sodiumbicarbonate, calcium phosphate or calcium citrate), a lubricant (e.g.,magnesium stearate, light anhydrous silicic acid, talc or sodium laurylsulfate), a flavoring agent (e.g., citric acid, menthol, glycine ororange powder), a preservative (e.g, sodium benzoate, sodium bisulfite,methylparaben or propylparaben), a stabilizer (e.g., citric acid, sodiumcitrate or acetic acid), a suspending agent (e.g., methylcellulose,polyvinyl pyrroliclone or aluminum stearate), a dispersing agent (e.g.,hydroxypropylmethylcellulose), a diluent (e.g., water), and base wax(e.g., cocoa butter, white petrolatum or polyethylene glycol). Theeffective amount of the TOR kinase inhibitor in the pharmaceuticalcomposition may be at a level that will exercise the desired effect; forexample, about 0.005 mg/kg of a patient's body weight to about 10 mg/kgof a patient's body weight in unit dosage for both oral and parenteraladministration.

The dose of a TOR kinase inhibitor and the dose of Compound AA to beadministered to a patient is rather widely variable and can be subjectto the judgment of a healthcare practitioner. In general, the TOR kinaseinhibitors and Compound AA can be administered one to four times a dayin a dose of about 0.005 mg/kg of a patient's body weight to about 10mg/kg of a patient's body weight in a patient, but the above dosage maybe properly varied depending on the age, body weight and medicalcondition of the patient and the type of administration. In oneembodiment, the dose is about 0.01 mg/kg of a patient's body weight toabout 5 mg/kg of a patient's body weight, about 0.05 mg/kg of apatient's body weight to about 1 mg/kg of a patient's body weight, about0.1 mg/kg of a patient's body weight to about 0.75 mg/kg of a patient'sbody weight or about 0.25 mg/kg of a patient's body weight to about 0.5mg/kg of a patient's body weight. In one embodiment, one dose is givenper day. In any given case, the amount of the TOR kinase inhibitoradministered will depend on such factors as the solubility of the activecomponent, the formulation used and the route of administration.

In another embodiment, provided herein are unit dosage formulations thatcomprise between about 1 mg and about 2000 mg, about 1 mg and about 200mg, about 35 mg and about 1400 mg, about 125 mg and about 1000 mg, about250 mg and about 1000 mg, about 500 mg and about 1000 mg, about 1 mg toabout 30 mg, about 1 mg to about 25 mg or about 2.5 mg to about 20 mg ofa TOR kinase inhibitor alone or in combination with Compound AA. Inanother embodiment, provided herein are unit dosage formulations thatcomprise 1 mg, 2.5 mg, 5 mg, 7.5 mg, 8 mg, 10 mg, 15 mg, 20 mg, 30 mg,35 mg, 45 mg, 50 mg, 70 mg, 100 mg, 125 mg, 140 mg, 175 mg, 200 mg, 250mg, 280 mg, 350 mg, 500 mg, 560 mg, 700 mg, 750 mg, 1000 mg or 1400 mgof a TOR kinase inhibitor alone or in combination with Compound AA. Inanother embodiment, provided herein are unit dosage formulations thatcomprise about 2.5 mg, about 7.5 mg, about 8 mg, about 10 mg, about 15mg, about 20 mg, about 30 mg or about 45 mg of a TOR kinase inhibitoralone or in combination with Compound AA.

In a particular embodiment, provided herein are unit dosage formulationscomprising about 7.5 mg, about 8 mg, about 10 mg, about 15 mg, about 30mg, about 45 mg, about 50 mg, about 75 mg, about 100 mg or about 400 mgof a TOR kinase inhibitor in combination with Compound AA. In aparticular embodiment, provided herein are unit dosage formulationscomprising about 5 mg, about 7.5 mg or about 10 mg of a TOR kinaseinhibitor in combination with Compound AA.

In certain embodiments, provided herein are unit dosage formulationscomprising about 25 mg, about 50 mg, about 75 mg, about 100 mg, about125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg or about250 mg of Compound AA alone or in combination with a TOR kinaseinhibitor.

In certain embodiments, provided herein are unit dosage formulationswherein the TOR kinase inhibitor:Compound AA ratio is from about 1:1 toabout 1:10. In certain embodiments, provided herein are unit dosageformulations wherein the TOR kinase inhibitor:Compound AA ratio is lessthan about 1:1, less than about 1:3 or less than about 1:10. In certainembodiments, provided herein are unit dosage formulations wherein theTOR kinase inhibitor:Compound AA ratio is about 1:1, about 1:3 or about1:10.

A TOR kinase inhibitor can be administered in combination with CompoundAA once, twice, three, four or more times daily.

A TOR kinase inhibitor can be administered in combination with CompoundAA orally for reasons of convenience. In one embodiment, whenadministered orally, a TOR kinase inhibitor in combination with CompoundAA is administered with a meal and water. In another embodiment, the TORkinase inhibitor in combination with Compound AA is dispersed in wateror juice (e.g., apple juice or orange juice) and administered orally asa suspension. In another embodiment, when administered orally, a TORkinase inhibitor in combination with Compound AA is administered in afasted state.

The TOR kinase inhibitor can also be administered in combination withCompound AA intravenously, such as intravenous infusion, orsubcutaneously, such as subcutaneous injection. The mode ofadministration is left to the discretion of the healthcare practitioner,and can depend in-part upon the site of the medical condition.

In one embodiment, provided herein are capsules containing a TOR kinaseinhibitor in combination with Compound AA without an additional carrier,excipient or vehicle.

In another embodiment, provided herein are compositions comprising aneffective amount of a TOR kinase inhibitor, an effective amount ofCompound AA, and a pharmaceutically acceptable carrier or vehicle,wherein a pharmaceutically acceptable carrier or vehicle can comprise anexcipient, diluent, or a mixture thereof. In one embodiment, thecomposition is a pharmaceutical composition.

The compositions can be in the form of tablets, chewable tablets,capsules, solutions, parenteral solutions, troches, suppositories andsuspensions and the like. Compositions can be formulated to contain adaily dose, or a convenient fraction of a daily dose, in a dosage unit,which may be a single tablet or capsule or convenient volume of aliquid. In one embodiment, the solutions are prepared from water-solublesalts, such as the hydrochloride salt. In general, all of thecompositions are prepared according to known methods in pharmaceuticalchemistry. Capsules can be prepared by mixing a TOR kinase inhibitorwith a suitable carrier or diluent and filling the proper amount of themixture in capsules. The usual carriers and diluents include, but arenot limited to, inert powdered substances such as starch of manydifferent kinds, powdered cellulose, especially crystalline andmicrocrystalline cellulose, sugars such as fructose, mannitol andsucrose, grain flours and similar edible powders.

Tablets can be prepared by direct compression, by wet granulation, or bydry granulation. Their formulations usually incorporate diluents,binders, lubricants and disintegrators as well as the compound. Typicaldiluents include, for example, various types of starch, lactose,mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such assodium chloride and powdered sugar. Powdered cellulose derivatives arealso useful. In one embodiment, the pharmaceutical composition islactose-free. Typical tablet binders are substances such as starch,gelatin and sugars such as lactose, fructose, glucose and the like.Natural and synthetic gums are also convenient, including acacia,alginates, methylcellulose, polyvinylpyrrolidine and the like.Polyethylene glycol, ethylcellulose and waxes can also serve as binders.Illustrative tablet formulations comprising Compound 1 are providedherein.

A lubricant might be necessary in a tablet formulation to prevent thetablet and punches from sticking in the die. The lubricant can be chosenfrom such slippery solids as talc, magnesium and calcium stearate,stearic acid and hydrogenated vegetable oils. Tablet disintegrators aresubstances that swell when wetted to break up the tablet and release thecompound. They include starches, clays, celluloses, algins and gums.More particularly, corn and potato starches, methylcellulose, agar,bentonite, wood cellulose, powdered natural sponge, cation-exchangeresins, alginic acid, guar gum, citrus pulp and carboxymethyl cellulose,for example, can be used as well as sodium lauryl sulfate. Tablets canbe coated with sugar as a flavor and sealant, or with film-formingprotecting agents to modify the dissolution properties of the tablet.The compositions can also be formulated as chewable tablets, forexample, by using substances such as mannitol in the formulation.

When it is desired to administer a TOR kinase inhibitor in combinationwith Compound AA as a suppository, typical bases can be used. Cocoabutter is a traditional suppository base, which can be modified byaddition of waxes to raise its melting point slightly. Water-misciblesuppository bases comprising, particularly, polyethylene glycols ofvarious molecular weights are in wide use.

The effect of the TOR kinase inhibitor in combination with Compound AAcan be delayed or prolonged by proper formulation. For example, a slowlysoluble pellet of the TOR kinase inhibitor in combination with CompoundAA can be prepared and incorporated in a tablet or capsule, or as aslow-release implantable device. The technique also includes makingpellets of several different dissolution rates and filling capsules witha mixture of the pellets. Tablets or capsules can be coated with a filmthat resists dissolution for a predictable period of time. Even theparenteral preparations can be made long-acting, by dissolving orsuspending the TOR kinase inhibitor in combination with Compound AA inoily or emulsified vehicles that allow it to disperse slowly in theserum.

In some embodiments, a pharmaceutically acceptable compositioncomprising Compound AA comprises from about 5% to about 60% of CompoundAA, or a pharmaceutically acceptable salt thereof, based upon totalweight of the composition. In some embodiments, a pharmaceuticallyacceptable composition comprising Compound AA comprises from about 5% toabout 15% or about 7% to about 15% or about 7% to about 10% or about 9%to about 12% of Compound AA, based upon total weight of the composition.In some embodiments, provided methods comprise administering to apatient in need thereof a pharmaceutically acceptable compositioncomprising from about 25% to about 75% or about 30% to about 60% orabout 40% to about 50% or about 40% to about 45% of Compound AA, basedupon total weight of the formulation. In certain embodiments, providedregimens comprise administering to a patient in need thereof apharmaceutically acceptable composition comprising from about 6%, about7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%,about 20%, about 30%, about 40%, about 41%, about 42%, about 43%, about44%, about 45%, about 50%, about 60%, about 70%, or about 75% ofCompound AA, based upon total weight of given composition orformulation.

In certain embodiments, Compound 1 is administered in a formulation setforth in U.S. Patent Application Publication No. 2013-0142873, publishedJun. 6, 2013, which is incorporated herein in its entirety (seeparticularly paragraph [0323] to paragraph [0424], and paragraph [0636]to paragraph [0655]). In other embodiments, Compound 1 is administeredin a formulation set forth in U.S. Provisional Patent Application No.61/828,506, filed May 29, 2013, which is incorporated herein in itsentirety (see particularly paragraph [0246] to paragraph [0403], andparagraph [0571] to paragraph [0586]).

In certain embodiments, the Compound 2 is administered in a formulationset forth in U.S. Provisional Application No. 61/813,064, filed Apr. 17,2013, which is incorporated herein in its entirety (see particularlyparagraph [0168] to paragraph [0189] and paragraph [0262] to paragraph[0294]). In other embodiments, the Compound 2 is administered in aformulation set forth in U.S. Provisional Patent Application No.61/911,201, filed Dec. 3, 2013, which is incorporated herein in itsentirety (see particularly paragraph [0170] to paragraph [0190], andparagraph [0264] to paragraph [0296]).

5.8 Kits

In certain embodiments, provided herein are kits comprising a TOR kinaseinhibitor and Compound AA.

In certain embodiments, provided herein are kits comprising one or moreunit dosage forms of a TOR kinase inhibitor, such as those describedherein, and one or more unit dosage forms of Compound AA, such as thosedescribed herein.

In some embodiments, the kits described herein additionally comprise ananti-CD-20 antibody, for example, rituximab (Rituxan® or MabThera®).

In certain embodiments, the kits provided herein further compriseinstructions for use, such as for administering a TOR kinase inhibitorand Compound AA.

6. EXAMPLES 6.1 Biochemical Assays

mTOR HTR-FRET Assay.

The following is an example of an assay that can be used to determinethe TOR kinase inhibitory activity of a test compound. TOR kinaseinhibitors were dissolved in DMSO and prepared as 10 mM stocks anddiluted appropriately for the experiments. Reagents were prepared asfollows:

“Simple TOR buffer” (used to dilute high glycerol TOR fraction): 10 mMTris pH 7.4, 100 mM NaCl, 0.1% Tween-20, 1 mM DTT. Invitrogen mTOR(cat#PV4753) was diluted in this buffer to an assay concentration of0.200 μg/mL.

ATP/Substrate solution: 0.075 mM ATP, 12.5 mM MnCl₂, 50 mM Hepes, pH7.4, 50 mM β-GOP, 250 nM Microcystin LR, 0.25 mM EDTA, 5 mM DTT, and 3.5μg/mL GST-p70S6.

Detection reagent solution: 50 mM HEPES, pH 7.4, 0.01% Triton X-100,0.01% BSA, 0.1 mM EDTA, 12.7 μg/mL Cy5-αGST Amersham (Cat#PA92002V), 9ng/mL α-phospho p70S6 (Thr389) (Cell Signaling Mouse Monoclonal #9206L),627 ng/mL α-mouse Lance Eu (Perkin Elmer Cat#AD0077).

To 20 μL of the Simple TOR buffer is added 0.5 μL of test compound inDMSO. To initiate the reaction 5 μL of ATP/Substrate solution was addedto 20 μL of the Simple TOR buffer solution (control) and to the compoundsolution prepared above. The assay was stopped after 60 min by adding 5μL of a 60 mM EDTA solution; 10 μL of detection reagent solution wasthen added and the mixture was allowed to sit for at least 2 hoursbefore reading on a Perkin-Elmer Envision Microplate Reader set todetect LANCE Eu TR-FRET (excitation at 320 nm and emission at 495/520nm).

TOR kinase inhibitors were tested in the TOR HTR-FRET assay and werefound to have activity therein, with certain compounds having an IC₅₀below 10 μM in the assay, with some compounds having an IC₅₀ between and0.005 nM and 250 nM, others having an IC₅₀ between and 250 nM and 500nM, others having an IC₅₀ between 500 nM and 1 μM, and others having anIC₅₀ between 1 μM and 10 μM.

DNA-PK Assay.

DNA-PK assay is performed using the procedures supplied in the PromegaDNA-PK assay kit (catalog #V7870). DNA-PK enzyme can be purchased fromPromega (Promega cat#V5811).

Selected TOR kinase inhibitors as described herein have, or are expectedto have, an IC₅₀ below 10 μM in this assay, with some TOR kinaseinhibitors as described herein having an IC₅₀ below 1 μM, and othershaving an IC₅₀ below 0.10 μM.

6.2 Cell Based Assays

DLBCL Cell Proliferation Assay.

DLBCL cell proliferation was assessed by the ³H-thymidine incorporationassay. Briefly, cells were cultured in 96-well cell culture plates inthe presence or absence of Compound 1, Compound AA (besylate salt), orboth. Each well contained 6000 cells/80 μL cell culture medium (RoswellPark Memorial Institute (RPMI)-1640+10-20% fetal bovine serum (FBS), 1%pen/strep/1% L-glutamine). Compound dilutions were made in 10× therequired final concentration, and 10 μL of each compound was added tothe cells in triplicate. The cells were treated with drugs in a finalconcentration of 0.2% dimethyl sulfoxide (DMSO) for all samples. Cellswere grown at 37° C. in a humidified incubator at 5% CO₂ for 72 hours inthe presence of the test compounds. One microcurie of ³H-thymidine (GEHealthcare, Fairfield, Conn.) was added to each well for the final 6hours of culture. The cells were harvested onto UniFilter-96 GF/C filterplates (PerkinElmer, Waltham, Mass.) using a cell harvester (Tomtec,Hamden, Conn.), and the plates were allowed to dry overnight. A total of25 μL/well of Microscint™-20 (PerkinElmer) was added and the plates wereanalyzed in TopCount NXT (PerkinElmer). Each well was counted for 1minute. The percentage inhibition of cell proliferation was calculatedby averaging all triplicates and normalizing to the DMSO control (0%inhibition). Final cumulative half-maximal inhibitory concentrations(IC₅₀) were calculated using non-linear regression and sigmoidal doseresponse, constraining the top to 100% and bottom to 0% and allowingvariable slope, using GraphPad Prism version 5.01. SEM (standard errorof the mean) was calculated from the individual IC₅₀s of each replicate.

Cell Lines.

The effect on cell proliferation of Compound 1 alone or in combinationwith Compound AA was evaluated on GCB DLBCL cell lines (SuDHL6, SuDHL10,HT, Farage, Pfeifer), ABC DLBCL cell lines (OCI-Ly10, U2932, OCI-Ly3),and DHIT (double hit, i.e. cMyc and Bcl-2 mutant) GCB DLBCL cell lines(Karpas 422, WSU-DLBCL2).

Data Analysis.

Theoretical additivity was calculated using the fractional productmethod and plotted as a separate curve. If the observed combinationeffect was greater than the theoretical additivity at two or moreconcentrations and error bars between theoretical additivity curve andcombination curves did not overlap, synergy was assigned. All data wasgenerated with n=3.

Results:

Synergy was observed upon treatment with the combination of Compound 1and Compound AA in the following DLBCL cell lines: SuDHL6, SuDHL10 andPfeiffer (GCB DLBCL sub types).

6.3 In Vivo Assays

DLBCL Xenograft Model.

Severe combined immunodeficiency (SCID) mice were implanted with humanDLBCL cell line (WSU-DLCL2) into the flank. Treatment of compoundsstarted between Day 11 and Day 14 after cell inoculation. Randomizedgroups of mice (n=9 to 10/group) were treated with the single agents(Compound 1, Compound A or Compound AA) or the combination of Compound1/Compound A, Compound A/Compound AA, or Compound 1/Compound AA.Compounds were administered orally on a once daily (Compound 1 andCompound A) or twice daily (C) schedule for 21 days. The positivecontrol consisted of CHOP therapy (combination of cyclophosphamide,doxorubicin, vincristine and prednisone). Compound 1 and Compound A wereformulated in CMC-Tween (carboxymethylcellulose/Tween 80/deionizedwater). Compound AA was suspended in DSP(dimethylsulphoxide/solutol/phosphate buffered saline).

Initial studies were conducted in order to determine the antitumoractivity of Compound 1 and to identify a dose level for the combinationstudies. In the WSU-DLCL2 xenograft model, Compound 1 inhibited tumorgrowth in a dose-dependent fashion. By the end of the 3-week dosingperiod, a 51%, 28%, and 22% tumor volume reduction (TVR) was observed in10, 3, and 1 mg/kg Compound 1-treated animals, respectively, whencompared with vehicle control (FIG. 1). In a subsequent combinationstudy, Compound 1 was dosed at 10 mg/kg, once daily (QD). Compound A andCompound AA were dosed at 30 mg/kg (QD) and 50 mg/kg (BID),respectively. In this combination study, Compound 1 and Compound Ademonstrated significant antitumor activity as single agents with a TVRof 29% and 30%, respectively, whereas Compound AA was inactive in thismodel (FIGS. 2-3). The combination of Compound 1 and Compound A produceda highly significant (p<0.001), synergistic inhibition of tumor growth(64%) in the WSU-DLCL2 xenograft model (FIG. 2). The antitumor activityof the combination of Compound 1 and Compound AA was not significantlydifferent from that of Compound 1 as a single agent (FIG. 3). Similarly,the antitumor activity of the combination of Compound A and Compound AAwas not significantly different from that of Compound A as a singleagent in the WSU-DLCL2 xenograft model.

OCI-Ly10 DLBCL Xenograft Model.

OCI-Ly10 cells are derived from a diffuse-large B-cell lymphoma, a typeof non-Hodgkins lymphoma. In brief, female CB.17 SCID mice areinoculated with 5×10⁶ OCI-Ly10 cells subcutaneously, and tumor areallowed to grow to approximately 50-300 mm³. The mice bearing xenograftwith similarly sized tumors are pooled together and randomized intovarious treatment groups. A typical efficacy study design involvesadministering one or more compounds at various dose levels andschedules, based on prior single agent studies, to tumor-bearing mice.Tumor volume is measured biweekly for approximately 28 days of treatmentusing calipers, and tumor volume is calculated using standard methods,for example, using the formula of W²×L/2. Tumor volume can optionally bemeasured further post-treatment. Statistical analysis will be performedusing standard statistical methods.

6.4 Clinical Protocol

A Phase 1B, Multi-Center, Open-Label Study of Novel Combinations andRituximab in Diffuse Large B Cell Lymphoma.

This study is a Phase 1B, multi-center, open-label study of the TORkinase inhibitor Compound 1, Compound A(3-(5-Amino-2-methyl-4-oxoquinazolin-3(4H)-yl)-piperidine-2,6-dione),and Compound AA(N-(3-(5-fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4-ylamino)phenyl)acrylamide),when administered in combination and in combination with rituximab, insubjects having Diffuse Large B Cell Lymphoma (DLBCL).

The primary objective of the study is to determine the safety andtolerability of Compound A, Compound 1 and Compound AA, whenadministered orally as doublets and in combination with rituximab, andto define the non-tolerated dose (NTD) and the maximum tolerated dose(MTD) of each combination. The secondary objectives of the study are toprovide information on the preliminary efficacy of each drug combinationand to characterize the pharmacokinetics (PK) of Compound A, Compound 1(and the M1 metabolite) and Compound AA following oral administration assingle agents and after combination treatment to assess drug-druginteractions.

Study Design.

This study is a phase 1B dose escalation clinical study of Compound A,Compound 1 and Compound AA administered orally as doublets, and astriplets in combination with rituximab, in subjects withrelapsed/refractory DLBCL who have failed at least one line of standardtherapy. The study will explore two drug doses for each novel agentusing a standard 3+3 dose escalation design with higher dose cohortsincluding the addition of a fixed dose of rituximab. Treatment armsinclude: Compound A+rituximab (Arm A), Compound A+Compound 1+/−rituximab(Arm B), Compound A+Compound AA+/−rituximab (Arm C) and CompoundAA+Compound 1+/−rituximab (Arm D).

All treatments will be administered in 28-day cycles. Compound A,Compound 1 and Compound AA, are administered orally on continuous dosingschedules either once daily (QD) or twice daily (BID) on days 1-28 ofeach 28-day cycle. Rituximab, when included in the regimen, will employa standard fixed dose (375 mg/m²) administered intravenously (IV) on Day1 of each 28-day cycle only. All three compounds will be explored at twodose levels including: Compound A (2.0 and 3.0 mg QD), Compound 1 (20and 30 mg QD), and Compound AA (375 and 500 mg BID). The highest twodoublet dose levels for Arms B, C, and D will explore the doublets withand without rituximab.

A standard “3+3” dose escalation design will be used to identify initialtoxicity of each combination. Subjects will be assigned to studytreatment arms based on Investigator choice and open slots. Cohorts of 3subjects will take study drugs in defined dose increments and, in theevent of dose-limiting toxicity (DLT) in 1 of 3 evaluable subjects,cohorts will be expanded to 6 subjects.

An evaluable subject for DLT is defined as one that received at least80% of the planned doses of Compound A, Compound 1 or Compound AA duringCycle 1; received at least 80% of the planned dose of rituximab duringCycle 1 (in rituximab containing cohorts only); and experienced studydrug-related DLT after receiving at least one dose of any study drug.Non-evaluable subjects not due to DLT will be replaced. Additionalsubjects within any dose cohort may be enrolled at the discretion of theSafety Review Committee (SRC).

A dose will be considered the non-tolerated dose (NTD) when 2 of 6evaluable subjects in a cohort experience drug-related DLT in Cycle 1.The maximum tolerated dose (MTD) is defined as the last dose level belowthe NTD with 0 or 1 out of 6 evaluable subjects experiencing DLT duringCycle 1. If 2 of 6 DLT are observed at the first dose level with eithercombination, a lower dose combination may be explored at the discretionof the SRC. An intermediate dose of Compound 1 (one between the NTD andthe last dose level before the NTD) may be evaluated to accuratelydetermine the MTD of the combination.

Following completion of dose escalation, selected combination treatmentarms may be expanded up to approximately 20 subjects per arm. Expansionmay occur at the MTD established in the dose escalation phase, or at analternative tolerable combination dose level, based on review of studydata.

Paired tumor biopsies for analysis of genetic abnormalities, geneexpression and biomarkers of treatment activity are optional in the doseescalation phase but mandatory during the dose expansion phase.

The study population will consist of men and women, 18 years or older,with relapsed or refractory DLBCL, with disease progression following atleast one standard first-line treatment regimen. Prior autologous stemcell transplant (greater than 3 months prior to enrollment) is allowed.

Enrollment is expected to take approximately 24 months (18 months fordose escalation, 6 months for expansion). Completion of active treatmentand post-treatment follow-up is expected to take 6-12 additional months.The entire study is expected to last approximately 3 years.

Dose levels to be explored in this Phase 1b study are shown below:

Arm A Arm B Arm C Arm D Cmpd A Ritux Cmpd A Cmpd 1 Ritux Cmpd A Cmpd AARitux Cmpd 1 Cmpd AA Ritux Dose (mg/ (mg/m² (mg (mg (mg/m² (mg/bid (mg(mg/m² (mg (mg bid (mg/m² Level daily) D1q28) daily) daily) D1q28)daily) daily) D1q28) daily) daily) D1q28) 1 2 375 2 20 2 375 20 375 2a 230 2 500 20 500 2b 2 30 375 2 500 375 20 500 375 3a 3 30 3 500 30 500 3b3 375 3 30 375 3 500 375 30 500 375

If unacceptable toxicity occurs at dose level 1, one starting dosereduction for Compound A (1 mg QD) and Compound 1 (15 mg QD) is allowed.No starting dose reductions for Compound AA are planned.

For Arms A and C, the Compound A dose will be reduced; for Arm D, theCompound 1 dose will be reduced. For Arm B, the safety review committee(SRC) will determine which of the two drugs in the doublet to dosereduce.

In Arm A (Compound A+rituximab), dose escalation will proceed from doselevel 1 to 3b, since only Compound A is escalated. In Arms B, C and Ddose levels 2b (doublet+rituximab) and 3a (dose escalation of doubletwithout rituximab) may be enrolled concurrently once dose level 2a(doublet) has been cleared. Both dose levels 2b and 3a must be clearedto move to dose level 3b.

Compound A, Compound 1 and Compound AA will be dosed daily and rituximabwill be dosed on Day 1 of each 28-day cycle. For both the doseescalation and expansion phases, slight modifications to the dosingschedule will occur during Cycle 1 in order to facilitate PK and PDevaluation of each drug alone and in combination. Starting with Cycle 2and thereafter, all oral drugs will start on Day 1 and continue throughDay 28 and rituximab will be administered on Day 1.

Administration of study drugs during Cycle 1 is described below:

In Arm B: Compound 1 will be initiated on Cycle 1 Day 1 followed by PKand PD sampling and continue through Day 28. Compound A will beinitiated on Cycle 1 Day 2 and continue through Day 28. Rituximab willbe administered on Cycle 1 Day 8.

In Arm C: Compound A will be initiated on Cycle 1 Day 1 followed by PKand PD sampling and continue through Day 28. Compound AA will beinitiated on Cycle 1 Day 2 and continue through Day 28. Rituximab willbe administered on Cycle 1 Day 8.

In Arm D: Compound 1 will be initiated on Cycle 1 Day 1 followed by PKand PD sampling and continue through Day 28. Compound AA will beinitiated on Cycle 1 Day 2 and continue through Day 28. Rituximab willbe administered on Cycle 1 Day 8.

After the first dose is administered on Day 1 in any cohort, subjectswill be observed for at least 28 days before the next higherprotocol-specified dose cohort can begin. Intra-subject dose escalationof study drugs is not permitted during Cycle 1 but may be permitted incycles beyond Cycle 1 if approved by the SRC. Dose reduction andtemporary interruption of one or both drugs due to toxicity is allowed,but dose reduction during Cycle 1 will constitute DLT.

Study treatment may be discontinued if there is evidence of diseaseprogression, unacceptable toxicity or subject/physician decision towithdraw. Subjects may continue to receive study drugs beyond diseaseprogression at the discretion of the Investigator.

The estimated total number of subjects to be enrolled during doseescalation is approximately 50 to 100, depending on cohort size.Approximately 30 to 60 additional subjects (10-20 per selected regimen)will be evaluated for safety, PK, PD, and preliminary antitumor effectsduring the expansion phase.

Subjects will be evaluated for efficacy after every 2 cycles throughCycle 6, every 3 cycles through Cycle 12 and every 6 months thereafter.All treated subjects will be included in the efficacy analyses. Theprimary efficacy variable is tumor response rate. Tumor response will bedetermined by the Investigator, based on International Workshop Criteria(IWC) for NHL/DLBCL.

The safety variables for this study include adverse events (AEs), safetyclinical laboratory variables, 12-lead electrocardiograms (ECGs), leftventricular ejection fraction (LVEF) assessments, physical examinations,vital signs, exposure to study treatment, assessment of concomitantmedications, and pregnancy testing for females of child bearingpotentials (FCBP).

During dose escalation, the decision to either evaluate a higher doselevel or declare an MTD will be determined by the SRC, based on theirreview of all available clinical and laboratory safety data for a givendose cohort.

The SRC will also select the dose and schedule of treatment regimens ofinterest for cohort expansion. One or more regimens may be selected forcohort expansion. The SRC will continue to review safety data regularlythroughout the study and make recommendations about study continuationand dose modification, as appropriate.

The concentration-time profiles of Compound A, Compound 1 and CompoundAA will be determined from serial blood samples collected afteradministration of study drugs as single agents and after combinationtreatment.

The effect of Compound A and Compound AA on Compound 1 and M1 PK will beassessed, as will the effect of Compound AA on Compound A PK. Systemicexposure of Compound A, Compound 1 and the M1 metabolite, and CompoundAA will be correlated with safety, PD and activity outcomes.

6.5 Clinical Protocol B

A Phase 1B, Multi-Center, Open-Label Study of Novel Combinations andRituximab in Diffuse Large B Cell Lymphoma.

This study is a Phase 1B, multi-center, open-label study of the TORkinase inhibitor Compound 1, Compound A(3-(5-Amino-2-methyl-4-oxoquinazolin-3(4H)-yl)-piperidine-2,6-dione),and Compound AA(N-(3-(5-fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4-ylamino)phenyl)acrylamide),when administered in combination and in combination with rituximab, insubjects having Diffuse Large B Cell Lymphoma (DLBCL).

The primary objective of the study is to determine the safety andtolerability of Compound A, Compound 1 and Compound AA, whenadministered orally as doublets and as triplets in combination withrituximab, determine the safety and tolerability of Compound A whenadministered in combination with rituximab, and to define thenon-tolerated dose (NTD) and the maximum tolerated dose (MTD) and/or therecommended phase 2 dose (RP2D) of each combination. The secondaryobjectives of the study are to provide information on the preliminaryefficacy of each drug combination and to characterize the steady statepharmacokinetics (PK) of Compound A, Compound 1 and Compound AAfollowing combination oral administration as single agents.

Study Design.

This study is a phase 1b dose escalation and expansion clinical study ofCompound A, Compound 1 and Compound AA administered orally as doublets,and as triplets in combination with rituximab, as well as a Compound Aplus rituximab doublet, in subjects with relapsed/refractory DLBCL whohave failed at least one line of standard therapy. The dose escalationphase of the study will explore one or more drug doses for each novelagent using a standard 3+3 dose escalation design with higher dosecohorts including the addition of a fixed dose of rituximab, followed byexpansion of selected cohorts of interest. The addition of rituximab canalso be evaluated at the doublet MTD if the higher dose levels are notreached. Treatment arms include: Compound A+Compound 1+/−rituximab (ArmA), Compound A+Compound AA+/−rituximab (Arm B), Compound AA+Compound1+/−rituximab (Arm C), and Compound A+rituximab (Arm D).

All treatments will initially be administered in 28-day cycles. CompoundA, Compound 1 and Compound AA, will initially be administered orally oncontinuous dosing schedules either once daily (QD) or twice daily (BID)on days 1 to 28 of each 28-day cycle. Rituximab, when included in theregimen, will be administered only once in each cycle as a standardfixed intravenous (IV) dose of 375 mg/m² on Day 8 of Cycle 1, and Day 1of each subsequent cycle. All three compounds will be explored at one ortwo dose levels including: Compound A (2.0 and 3.0 mg QD), Compound 1(20 and 30 mg QD), and Compound AA (500 mg BID). The highest two doubletdose levels (or the MTD if at a lower dose level) will explore thecombinations with rituximab.

A standard “3+3” dose escalation design will be used to identify initialtoxicity of each combination. Subjects will be assigned to studytreatment arms based on investigator choice and open slots. Cohorts of 3subjects will take study drugs in defined dose increments and, in theevent of dose-limiting toxicity (DLT) in 1 of 3 evaluable subjects,cohorts will be expanded to 6 subjects.

An evaluable subject for DLT is defined as one that received at least80% of the planned doses of Compound A, Compound 1 or Compound AA duringCycle 1 without experiencing a DLT, and received at least 80% of theplanned dose of rituximab during Cycle 1 (in rituximab containingcohorts only); without experiencing a DLT, or experienced a DLT afterreceiving at least one dose of any study drug. Non-evaluable subjectswill be replaced. Additional subjects within any dose cohort may beenrolled at the discretion of the Safety Review Committee (SRC).

A dose will be considered the NTD when 2 of 6 evaluable subjects in acohort experience a drug-related DLT in Cycle 1. The MTD is defined asthe last dose level(s) below the NTD with 0 or 1 out of 6 evaluablesubjects experiencing a DLT during Cycle 1. If 2 of 6 DLTs are observedat the first dose level with either combination, a lower dosecombination may be explored at the discretion of the SRC. Anintermediate dose of study drugs (one between the NTD and the last doselevel before the NTD) may be evaluated to accurately determine the MTDof the combination. Alternative schedules reducing the total exposure ofstudy drug during a cycle may also be evaluated for tolerability.

Following completion of dose escalation, selected combination treatmentarms may be expanded up to approximately 20 subjects per arm. Expansionmay occur at the MTD established in the dose escalation phase, or at analternative tolerable combination dose level, based on review of studydata.

Paired tumor biopsies for analysis of genetic abnormalities, RNA andprotein expression, and biomarkers of treatment activity are optional inthe dose escalation phase but mandatory during the dose expansion phase.

The study population will consist of men and women, 18 years or older,with relapsed or refractory DLBCL, with disease progression following atleast two prior standard treatment regimens and autologous stem celltransplant (ASCT) in chemotherapy sensitive patients are eligible.Enrollment will also include selected high-risk subjects prior to ASCTand subjects not otherwise eligible for ASCT.

Inclusion Criteria:

Subjects must satisfy all of the following criteria to be enrolled inthe study: (1) Understand and voluntarily sign an informed consentdocument prior to conducting any study related assessments orprocedures; (2) Consent to retrieve archival tumor tissue for analysis(in the event that archival tissue is not available an exception may begranted by the Sponsor); (3) Consent to undergo paired tumor biopsies(Screening and on treatment) for genetic analysis and biomarkerevaluation (expansion cohorts only) (waiver to this requirement may begiven under exceptional circumstances); (4) Men and women, 18 years orolder, with histologically or cytologically-confirmed, relapsed orrefractory DLBCL (including transformed low grade lymphoma) following atleast two prior standard treatment regimens (eg, R—CHOP or similarfirst-line regimen and at least one second-line salvage regimen) andASCT in chemotherapy sensitive patients, with the following exceptions:(i) Subjects in the pre-ASCT setting with poor prognosis, defined asprimary refractory disease, relapse within 12 months followingfirst-line treatment, “double-hit” lymphomas with Bcl-2/Myc generearrangements or overexpression, or high IPI score (2,3) at relapse;(ii) Subjects age >65 refusing, or not otherwise appropriate, per theInvestigator's judgment, for ASCT; (5) At least one site of measurabledisease (>1.5 cm in the long axis or >1.0 cm in both the long and shortaxis); (6) ECOG PS of 0 or 1; (7) Subjects must have the followinglaboratory values: (i) Absolute Neutrophil Count (ANC) ≧1.5×10⁹/Lwithout growth factor support for 7 days; (ii) Hemoglobin (Hgb) ≧8 g/dL;(iii) Platelets (plt) ≧50×10⁹/L without transfusion for 7 days (14 daysif received pegfilgrastim); (iv) Potassium within normal limits orcorrectable with supplements; (v) AST/SGOT and ALT/SGPT ≦2.5× UpperLimit of Normal (ULN) or ≦5.0× ULN if liver tumor is present; (vi) Serumbilirubin ≦1.5×ULN; (vii) Estimated serum creatinine clearance of ≧50mL/min using the Cockcroft-Gault equation; (8) Females of childbearingpotential (FCBP) (A female of childbearing potential is a sexuallymature woman who 1) has not undergone a hysterectomy (the surgicalremoval of the uterus) or bilateral oophorectomy (the surgical removalof both ovaries) or 2) has not been naturally postmenopausal for atleast 24 consecutive months (ie, has had menses at any time during thepreceding 24 consecutive months) must: (i) Agree to use at least twoeffective contraceptive methods (oral, injectable, or implantablehormonal contraceptive; tubal ligation; intra-uterine device; barriercontraceptive with spermicide; or vasectomized partner), one of whichmust be barrier, throughout the study, and for up to 28 days followingthe last dose of study drug; (ii) Have a negative serum pregnancy test(sensitivity of at least 25 mIU/mL) at Screening; (iii) Have a negativeserum or urine pregnancy test (investigator's discretion) within 72hours prior to Cycle 1 Day −1 of study treatment (note that theScreening serum pregnancy test can be used as the test prior to Day −1study treatment if it is performed within the prior 72 hours); (iv)Avoid conceiving for 28 days after the last dose of any study drug; (v)Agree to ongoing pregnancy testing during the course of the study; (9)Males must practice complete abstinence or agree to use a condom (alatex condom is recommended) during sexual contact with a pregnantfemale or a female of childbearing potential and will avoid conceivingwhile participating in the study, during dose interruptions, and for atleast 28 days following study drug discontinuation, even if he hasundergone a successful vasectomy; (10) All subjects enrolled intotreatment arms receiving Compound A must: (i) Understand that the(investigational product) IP could have a potential teratogenic risk;(ii) Agree to abstain from donating blood or sperm while taking IP andfor at least 28 days following discontinuation of IP; (iii) Agree not toshare IP with another person; (iv) Be counseled about pregnancyprecautions and risks of fetal exposure and agree to requirements ofPPRMP; (11) Able to adhere to the study visit schedule and otherprotocol requirements.

Exclusion Criteria:

The presence of any of the following will exclude a subject fromenrollment: (1) Symptomatic central nervous system involvement; (2)Known symptomatic acute or chronic pancreatitis; (3) Persistent diarrheaor malabsorption ≧NCI CTCAE grade 2, despite medical management; (4)Peripheral neuropathy ≧NCI CTCAE grade 2; (5) Impaired cardiac functionor clinically significant cardiac diseases, including any of thefollowing: (i) LVEF <45% as determined by MUGA or ECHO; (ii) Completeleft bundle branch or bifascicular block (iii) Congenital long QTsyndrome; (iv) Persistent or clinically meaningful ventriculararrhythmias; (v) QTcF >460 msec on Screening ECG (mean of triplicaterecordings); (vi) Unstable angina pectoris or myocardial infarction ≦3months prior to starting study drugs; (vii) Troponin-T value >0.4 ng/mlor BNP >300 pg/mL (Subjects with baseline troponin-T >ULN or BNP >100pg/mL are eligible but must have cardiologist evaluation prior toenrollment in the trial for baseline assessment and optimization ofcardioprotective therapy); (6) Subjects with diabetes on activetreatment or subjects with either of the following (for subjects treatedon Compound 1 containing arms only): (i) Fasting blood glucose (FBG)≧126 mg/dL (7.0 mmol/L); (ii) HbA1c ≧6.5%; (7) Prior ASCT ≦3 monthsbefore first dose; (8) Prior allogeneic stem cell transplant with eitherstandard or reduced intensity conditioning; (9) Prior systemiccancer-directed treatments or investigational modalities ≦5 half livesor 4 weeks prior to starting study drugs, whichever is shorter; (10)Prior treatment with a dual mTORC1/mTORC2 inhibitor (Compound 1 only) orBTK inhibitor (Compound AA arms only) (Prior treatment with rapamycinanalogues, PI3K or AKT inhibitors, lenalidomide and rituximab areallowed); (11) Subjects who have undergone major surgery ≦2 weeks priorto starting study drugs (subjects must have recovered from any effectsof recent surgery or therapy that might confound the safety evaluationof study drug; no specific washout is required for radiotherapy); (12)Women who are pregnant or breast feeding (adults of reproductivepotential not employing two forms of birth control); (13) Subjects withknown HIV infection; (14) Subjects with known chronic active hepatitis Bor C virus (HBV/HCV) infection; (15) Subjects with treatment-relatedmyelodysplastic syndrome; (16) Chronic use of proton pump inhibitors orH2 antagonists or their use within 7 days of first dose for subjectstreated on Compound AA-containing arms (B and C). Subjects with chronicgastroesophageal reflux disease, dyspepsia, and peptic ulcer disease,should be carefully evaluated for their suitability for this treatmentprior to enrollment in this study (these medications are prohibitedconcomitant medications throughout the study); (17) Any othersignificant medical condition, laboratory abnormality, or psychiatricillness which places the subject at unacceptable risk or that wouldprevent the subject from complying with the study; (18) History ofconcurrent second cancers requiring active, ongoing systemic treatment.

Enrollment is expected to take approximately 24 months to complete (18months for dose escalation, and 6 months for expansion). Completion ofactive treatment and post-treatment follow-up is expected to take—anadditional 6-12 months. The entire study is expected to lastapproximately 3 years.

The End of Trial is defined as either the date of the last visit of thelast subject to complete the study, or the date of receipt of the lastdata point from the last subject that is required for primary, secondaryand/or exploratory analysis, as pre-specified in the protocol and/or theStatistical Analysis Plan, whichever is the later date.

Dose levels to be explored in this Phase 1b study are shown below:

Arms A, B, C, D Arm A Arm B Arm C Arm D Ritux Dose Cmpd A Cmpd 1 Cmpd ACmpd AA Cmpd 1 Cmpd AA Cmpd A (mg/m²) Level (mg QD) (mg QD) (mg QD) (mgBID) (mg QD) (mg BID) (mg QD) (q 28) 1 2 20 — — — — — 2 2 30 2 500 20500 — 3 2 30 2 500 20 500 2 375 4 3 30 3 500 30 500 3 375 BID = twice aday; QD = once a day; q 28 = once every 28 days (Day 8 in Cycle 1; Day 1in subsequent cycles); Ritux = rituximab

All treatment cycles are 28 days in length. Dosing will start at DoseLevel 1 for Arm A, Dose Level 2 for Arms B and C and Dose Level 3 forArm D. Each dose level must clear before initiating the next higher doselevel. If unacceptable toxicity occurs at the initial dose level, dosereductions for Compound A (1.5 mg QD and 1 mg QD) and Compound 1 (15 mgQD) are allowed. Additionally, exploration of an alternative schedule ofCompound A (daily for 5 out of 7 days) is allowed based on SRC review.No starting dose reductions for Compound AA are planned.

For Arms B and D, the Compound A dose will be reduced; for Arm C, theCompound 1 dose will be reduced. For Arm A, the SRC will determine whichof the two drugs in the doublet to dose reduce.

Compound A, Compound 1 and Compound AA will be dosed daily on acontinuous basis in 28-day cycles. Compound A dosing may be modified to5 out of 7 days based on SRC review (the cycle length will remain 28days). To minimize the risk of tumor lysis syndrome, rituximab, whenadministered, will be dosed on Day 8 of Cycle 1, then on Day 1 of eachsubsequent cycle.

After the first dose is administered on Day 1 in any cohort, subjectswill be observed for at least 28 days before the next higherprotocol-specified dose cohort can begin. Intra-subject dose escalationof study drugs is not permitted during Cycle 1 but may be permitted inlater cycles if approved by the SRC. Dose reduction and temporaryinterruption of one or both drugs due to toxicity is allowed, but dosereduction during Cycle 1 will constitute DLT.

Study treatment may be discontinued if there is evidence of diseaseprogression, unacceptable toxicity or subject/physician decision towithdraw. Subjects may continue to receive study drugs beyond diseaseprogression at the discretion of the Investigator.

The estimated total number of subjects to be enrolled during doseescalation is approximately 36 to 72, depending on cohort size.Approximately 40 to 80 additional subjects (10 to 20 per selectedregimen) will be evaluated for safety, PK, PD, and preliminary antitumoreffects during the expansion phase.

Subjects will be evaluated for efficacy after every 2 cycles throughCycle 6, every 3 cycles through Cycle 12 and every 6 months thereafter.All treated subjects will be included in the efficacy analyses. Theprimary efficacy variable is tumor response rate and duration. Tumorresponse will be determined by the Investigator, based on InternationalWorkshop Criteria (IWC) for Malignant Lymphoma (Cheson et al, J ClinOncol, 2007, 25 (5): 579-586).

Secondary and exploratory endpoints include evaluation of Compound A,Compound 1, and Compound AA pharmacodynamic and predictive biomarkers inblood and/or tumor and exploration of PK, PD, toxicity, and activityrelationships

The safety variables for this study include adverse events (AEs), safetyclinical laboratory variables, 12-lead electrocardiograms (ECGs),Eastern Cooperative Oncology Group performance status (ECOG-PS), leftventricular ejection fraction (LVEF) assessments, physical examinations,vital signs, exposure to study treatment, assessment of concomitantmedications, and pregnancy testing for females of child bearingpotential (FCBP).

During dose escalation, the decision to either evaluate a higher doselevel or declare an MTD will be determined by the SRC, based on theirreview of all available clinical and laboratory safety data for a givendose cohort.

The SRC will also select the dose and schedule and treatment regimens ofinterest for cohort expansion. One or more regimens may be selected forcohort expansion. The SRC will continue to review safety data regularlythroughout the study and make recommendations about study continuationand dose modification, as appropriate.

The steady-state plasma pharmacokinetics of Compound A, Compound 1, theM1 metabolite of Compound 1, and Compound AA will be determined in ArmC. Sparse plasma concentrations of Compound A, Compound 1, and CompoundAA will be evaluated after single dose administration of drugcombinations and at steady state in all arms (except dose level 2 in ArmC, which will undergo intensive PK monitoring at steady state).Correlations of drug exposure with safety, PD and clinical endpoints mayalso be explored as an exploratory endpoint.

Pharmacodynamic biomarkers of each novel agent at baseline and on studytreatment will be explored, including: 1) Compound A, modulation of CRBNsubstrates in B and T cells; 2) Compound 1, mTOR signaling pathwaybiomarkers (p4E-BP1, pAKT, and possibly others); 3) Compound AA, B-cellreceptor signaling pathway biomarkers (pBTK, pERK, and possibly others).

Overview of Statistical Methodology.

Statistical analyses will be performed by study phase, treatment arm,and dose level as needed or applicable. All analyses will be descriptivein nature. The efficacy variable of primary interest is tumor responseand duration. Other preliminary efficacy variables, including (FDG)-PEToutcomes will be summarized using frequency tabulations for categoricalvariables or descriptive statistics for continuous variables. Efficacyanalysis will be repeated for enrolled, treated and efficacy evaluablepopulations, with the result using treated population consideredprimary. All summaries of safety data will be conducted using subjectsreceiving at least one dose of Study Drug (the Safety Population).

All biomarker-related data presentations will be based on treatedsubjects with at least one baseline and one on-study evaluation (thebiomarker evaluable population), unless specified otherwise. Descriptivestatistics will be presented for baseline and change from baseline ofcontinuous biomarker endpoints, by treatment arm and overall.

During the dose escalation phase, approximately 36 to 72 subjects willbe enrolled. After that, up to 20 subjects may be enrolled in each ofthe selected cohorts during the dose expansion phase. Since the primaryobjective of this study is to determine safety/tolerability andMTD/RP2D, an exact sample size for either phase will not be stated inadvance.

6.6 Compound Formulations

Illustrative formulations of Compound 1 useful in the methods providedherein are set forth in Tables 1-4, below.

TABLE 1 Amounts Ingredients mg % w/w Compound 1 20.0 15.38 Lactosemonohydrate, NF (Fast Flo 316) 63.98 49.22 Microcrystalline cellulose,NF (Avicel pH 102) 40.30 31.00 Croscarmellose sodium, NF (Ac-Di-Sol)3.90 3.00 Stearic acid, NF 0.52 0.40 Magnesium Stearate, NF 1.30 1.00Total 130.0 100 Opadry yellow 03K12429 5.2 4.0

TABLE 2 Amounts Ingredients mg % w/w Compound 1 5.0 3.80 Lactosemonohydrate, NF (Fast Flo 316) 78.98 60.70 Microcrystalline cellulose,NF (Avicel pH 102) 40.30 31.00 Croscarmellose sodium, NF (Ac-Di-Sol)3.90 3.00 Stearic acid, NF 0.52 0.40 Magnesium Stearate, NF 1.30 1.00Total 130.0 100 Opadry II pink 85F94211 5.2 4% weight gain

TABLE 3 Amounts Ingredients mg % w/w Compound 1 15.0 20.0 30.0 15.38Lactose monohydrate, NF (Fast Flo 48.37 64.50 96.75 49.62 316)Microcrystalline cellulose, NF 30.23 40.30 60.45 31.00 (Avicel pH 112)Croscarmellose sodium, NF 2.925 3.90 5.85 3.00 (Ac-Di-Sol) MagnesiumStearate, NF 0.975 1.30 1.95 1.00 Total 97.50 130.0 195.00 100 Opadryyellow 03K12429 3.9 4.0 Opadry II Pink 85F94211 5.2 4.0 Opadry Pink03K140004 7.8 4.0

TABLE 4 Amounts Ingredients mg % w/w Compound 1 45.00 15.38 Lactosemonohydrate, NF (Fast Flo 316) 143.955 49.22 Microcrystalline cellulose,NF (Avicel pH 102) 90.675 31.00 Croscarmellose sodium, NF (Ac-Di-Sol)8.775 3.00 Stearic acid, NF 1.170 0.40 Magnesium Stearate, NF 2.925 1.00Total 292.50 100 Opadry pink 03K140004 11.70 4.0

Illustrative formulations of Compound 2 useful in the methods providedherein are set forth in Table 5, below.

TABLE 5 Exemplary Tablet Formulations % w/w (mg) Batch # Ingredients 1 23 4 Compound 2 10 10 10 10 (active ingredient) Mannitol (Mannogem EZ) qsqs qs qs Microcrystalline Cellulose 25 25 25 25 (PH 112) Sodium StarchGlycolate 3 3 3 3 Silicon dioxide 1 1 1 1 Stearic acid 0.5 0.5 0.5 0.5Disodium EDTA 0.5 0.5 BHT 0.4 0.4 Magnesium Stearate 0.65 0.65 0.65 0.65Total 100 100 100 100 Color Yellow Yellow Yellow Yellow

Illustrative formulations of Compound AA useful in the methods providedherein are set forth in Table 6, below.

TABLE 6 Components of N-(3-(5-fluoro-2-(4-(2-methoxyethoxy)phenylamino)-pyrimidin-4-ylamino)phenyl)acrylamide besylate capsules First GenerationCapsules Second Generation Capsules Component Amount per Amount perAmount per Amount per 25 mg 125 mg 25 mg 125 mg Capsule shell CapsuleCapsule Capsule Capsule 1, size 0 dark 1, size 0 1, size 0 1, size 0green capsule white capsule white capsule white capsuleN-(3-(5-fluoro-2-(4-(2- 34.97 mg 174.86 mg 34.97 mg 174.30 mgmethoxyethoxy)phenylamino)pyrimidin-4- (25 mg free (125 mg free (25 mgfree (125 mg ylamino)phenyl) base) base) base) free base) acrylamidebesylate Microcrystalline cellulose 186.03 mg 105.27 mg 186.03 mg 101.68mg Lactose monohydrate 32.50 mg 41.50 mg 32.50 mg 41.50 mg Sodium starchglycolate 32.50 mg 41.50 mg 32.50 mg 41.50 mg Poloxamer 407 32.50 mg41.50 mg 32.50 mg 41.50 mg Fumed silica 3.25 mg 4.15 mg 3.25 mg 4.15 mgMagnesium stearate 3.25 mg^(†) 6.23 mg{circumflex over ( )} 3.25 mg^(†)10.38 mg^(‡) ^(†)0.5% (1.625 mg) intragranular; 0.5% (1.625 mg)extragranular. {circumflex over ( )}0.5% (2.08 mg) intragranular; 1.0%(4.15 mg) extragranular. ^(‡)2.0% (8.30 mg) intragranular; 0.5% (2.08mg) extragranular.

A number of references have been cited, the disclosures of which areincorporated herein by reference in their entirety. The embodimentsdisclosed herein are not to be limited in scope by the specificembodiments disclosed in the examples which are intended asillustrations of a few aspects of the disclosed embodiments and anyembodiments that are functionally equivalent are encompassed by thepresent disclosure. Indeed, various modifications of the embodimentsdisclosed herein are in addition to those shown and described hereinwill become apparent to those skilled in the art and are intended tofall within the scope of the appended claims.

What is claimed is:
 1. A method for treating diffuse large B-cell lymphoma, comprising administering an effective amount of a TOR kinase inhibitor in combination with an effective amount of N-(3-(5-fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4-ylamino)phenyl)acrylamide, or a pharmaceutically acceptable salt thereof, to a patient having diffuse large B-cell lymphoma, wherein the TOR kinase inhibitor is 7-(6-(2-hydroxypropan-2-yl)-pyridin-3-yl)-1-((1r,4r)-4-methoxycyclohexyl)-3,4-dihydropyrazino-[2,3-b]pyrazin-2(1H)-one or a pharmaceutically acceptable salt, stereoisomer, tautomer or isotopologue thereof.
 2. The method of claim 1, wherein the diffuse large B-cell lymphoma is associated with the pathways involving mTOR, PI3K, or Akt kinases and mutants or isoforms thereof.
 3. The method of claim 1, wherein the TOR kinase inhibitor is administered in combination with a besylate salt of N-(3-(5-fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4-ylamino)phenyl)acrylamide.
 4. The method of claim 1, wherein the TOR kinase inhibitor is administered in combination with the free base of N-(3-(5-fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4-ylamino)phenyl)acrylamide.
 5. The method of claim 1, further comprising the administration of an anti-CD20 antibody.
 6. The method of claim 5, wherein anti-CD20 antibody is rituximab. 